Tag: Breast Cancer

FDA Approves DATROWAY® for Advanced Metastatic HR-Positive, HER-Negative Breast Cancer

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SUMMARY: The FDA on January 17, 2025, approved Datopotamab deruxtecan-dlnk (DATROWAY®, Dato-DXd)), a Trop-2-directed antibody and topoisomerase inhibitor conjugate, for adult patients with unresectable or metastatic, Hormone Receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative (IHC 0, IHC1+ or IHC2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease.

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 in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence. Approximately 70% of breast tumors in patients with metastatic disease are Estrogen Receptor (ER) and/or Progesterone Receptor (PR) positive and HER2-negative. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or chemotherapy. Resistance to hormonal therapy occurs in a majority of the patients and there is therefore an unmet need for agents with novel mechanisms of action.

Datopotamab-deruxtecan (Dato-DXd) is an ADC composed of a TROP2-directed monoclonal antibody conjugated to a potent topoisomerase I inhibitor via a stable tetrapeptide-based cleavable linker. Trop-2 is a transmembrane calcium signal transducer that stimulates cancer cell growth. TROP-2 is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. It has been associated with poor Overall and Disease-Free Survival in several types of solid tumors. TROP-2 is expressed in more than 85% of breast tumors including Triple Negative Breast Cancer. Upon binding to TROP-2, the anti-TROP-2 monoclonal antibody is internalized and delivers the payload directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables the payload to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Dato-DXd showed encouraging antitumor activity in the TROPION-PanTumor01 trial, an ongoing multicenter, open-label study, evaluating Dato-DXd in different dose levels in solid tumors.

The present FDA approval was based on TROPION-Breast01, which is an open-label, global, Phase III study in which 732 patients (N=732) with HR-positive, HER2-negative previously treated metastatic breast cancer were randomly assigned in a 1:1 ratio to receive either Dato-DXd (N=365) or investigators choice of chemotherapy (N=367). Dato-DXd was given at a dose of 6 mg/kg IV on day 1 every 3 weeks. Investigator choice of chemotherapy consisted of Eribulin mesylate, Vinorelbine, or Gemcitabine, all given IV on days 1 and 8 every 3 weeks, as well as Capecitabine given orally on days 1-14 every 3 weeks. Treatment continued until disease progression or unacceptable toxicities. The median age was 55 yrs, and enrolled patients had received 1 or 2 prior lines of chemotherapy in the inoperable or metastatic setting. Eligible patients had progressed on or were deemed unsuitable for endocrine therapy. Patients were stratified by the number of lines of chemotherapy received in the unresectable/metastatic setting, and treatment with a previous CDK4/6 inhibitor. The Co-Primary end points were Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) and Overall Survival (OS). Secondary end points included Overall Response Rate (ORR), Safety, Patient Reported Outcomes (PRO), and Time to First Subsequent Therapy (TFST).

The Median PFS by BICR in the Dato-DXd arm was 6.9 months versus 4.9 months in the chemotherapy arm (HR=0.63; P < 0.0001). The PFS benefit with Dato-DXd over chemotherapy was noted irrespective of brain metastases and prior duration of treatment with CDK4/6 inhibitors. Although OS data were immature, a trend favoring Dato-DXd was observed. The confirmed ORR was 36.4% and 22.9% and median Duration of Response was 6.7 months and 5.7 months in the Dato-DXd and chemotherapy groups, respectively. The median Time to First Subsequent Therapy was 8.2 months with Dato-DXd and 5.0 months with chemotherapy. Dato-DXd also demonstrated a delay in time to deterioration in global health status/quality of life, compared to chemotherapy. Grade 3 or more treatment-related adverse events with Dato-DXd was lower than with chemotherapy (20.8% versus 44.7%) and the most common toxicities were nausea and stomatitis with Dato-DXd and neutropenia in the chemotherapy arm.

In conclusion, patients receiving Dato-DXd showed statistically significant and clinically meaningful improvement in Progression Free Survival compared to chemotherapy, with a favorable and manageable safety profile. The improved outcomes were observed across subgroups, supporting the benefit of this novel treatment option, for previously treated patients with inoperable/metastatic HR-positive, HER2-negative breast cancer.

Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Primary Results From TROPION-Breast01. Bardia A, Jhaveri K, Im S-A, et al. for the TROPION-Breast01 Investigators. J Clin Oncol. 2025;43:285-296.

Prolonged Survival Benefit with LYNPARZA® in BRCA Mutated 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. Approximately 319,750 new cases of breast cancer will be diagnosed in 2025 and about 42,680 individuals will die of the disease, largely due to metastatic recurrence.

DNA can be damaged due to errors during its replication or as a result of environmental exposure to UV radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. Mutations in BRCA1 and BRCA2 account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation, and the deleterious effects of the mutations are seen even when a second copy of the gene in an individual is normal. Patients with BRCA mutations can present with aggressive, high-risk disease and are at a high risk of recurrence following completion of multimodality therapy including surgery, radiation, and chemotherapy. This is an area of unmet need, warranting identification of additional novel and effective therapies.

BRCA1 and BRCA2 are tumor suppressor genes and they recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. The PARP (Poly ADP Ribose Polymerase) family of enzymes include PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive.

Olaparib (LYNPARZA®) is a PARP inhibitor, that traps PARP onto DNA at sites of single-strand breaks, thereby preventing their repair and generate double-strand breaks. These breaks cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death.

OlympiA is a multicenter, randomized, placebo-controlled, double-blind, Phase III trial of adjuvant Olaparib after neoadjuvant/adjuvant chemotherapy, in patients with germline BRCA1/2 mutations, and high risk HER2-negative early breast cancer. This trial enrolled 1836 patients, including triple-negative and Hormone Receptor positive (HR-positive) breast cancer. All enrolled patients had already received standard adjuvant or neoadjuvant chemotherapy, surgery and if needed, radiation therapy, for early stage breast cancer (Stage II-III). Inclusion criteria required that patients have a high risk of disease recurrence. Patients with triple-negative breast cancer who received adjuvant chemotherapy were required to have axillary node–positive disease or an invasive primary tumor measuring at least 2 cm. Patients who were treated with neoadjuvant chemotherapy were required to have residual invasive breast cancer in the breast or resected lymph nodes (no pathological Complete Response from neoadjuvant therapy). Patients who were treated with adjuvant chemotherapy for HR-positive, HER2-negative breast cancer were required to have 4 or more pathologically confirmed positive lymph nodes. Patients were randomized 1:1 to receive Olaparib 300 mg PO BID continuously for 1 year (N=921) or placebo (N=915). Endocrine therapy and bisphosphonates were allowed. Treatment groups were well balanced. The median age was 42 years, germline mutations were present in BRCA1 in 72% of the patients, in BRCA2 in 27% of the patients, 82% of the patients had triple-negative breast cancer, 18% had HR-positive and HER2 negative disease, 62% were premenopausal and 38% were postmenopausal, 50% of the patients had received adjuvant chemotherapy and 50% had received neoadjuvant chemotherapy. The Primary endpoint was Invasive Disease Free Survival (IDFS) and Secondary endpoints included Distant DFS (DDFS), Overall Survival (OS) and Safety. At the pre-specified interim analysis (2.5 years), the estimated 3-year Invasive DFS was 85.9% for patients who received Olaparib compared with 77.1% for those who received placebo (HR=0.58; P<0.001), representing a 42% reduction in the risk of Invasive DFS with Olaparib compared to placebo. The 3-year Distant DFS was 87.5% versus 80.4% respectively (HR=0.57; P<0.001). The researchers in this updated analysis reported the results of the third pre-specified interim analysis with median follow-up of 6.1 years (maximum follow-up of 9.6 years).

The treatment benefit with Olaparib was maintained with longer follow up, and was similar to previously reported results. The Invasive DFS at 6 years was 79.6% in the Olaparib-treated group versus 70.3% in the placebo group, with an absolute difference of 9.3%, favoring the addition of Olaparib (HR=0.65). The Distant DFS at 6 years was 83.5% versus 75.7%, respectively, with an absolute difference of 7.8% (HR=0.65). The 6-year Overall Survival rate was 87.5% in the Olaparib group versus 83.2% in the placebo group, with a 28% reduction in the risk of death (HR=0.72). The benefit with adjuvant Olaparib was consistent across all key subgroups, including for patients with high risk and HR-positive disease.

Fewer cases of BRCA-associated cancers such as contralateral invasive and non-invasive breast cancers, new primary ovarian cancer and new primary fallopian tube cancer were reported, with adjuvant Olaparib versus placebo. Further, there was no increase in the risk of developing secondary myelodysplastic syndrome or acute myeloid leukemia.

It was concluded that at 6.1 years median follow-up, one year of adjuvant treatment with Olaparib after neoadjuvant or adjuvant chemotherapy continues to demonstrate meaningful improvements in Invasive DFS, Distant DFS and OS in patients with germline BRCA pathogenic variants and high risk, HER2-negative breast cancer, including those with HR-positive tumors. This study highlights the importance of BRCA testing in early stage breast cancer. Perhaps considering one year of adjuvant Olaparib followed by a CDK4/6 inhibitor in HR-positive, BRCA-positive, high risk HER2-negative early stage breast cancer patients, may be a reasonable approach.

Garber J: OlympiA-Phase 3, multicenter, randomized placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/BRCA2 pathogenic variants and high-risk HER2-negative primary breast cancer: Longer-term follow-up. 2024 San Antonio Breast Cancer Symposium. Abstract GS1-09. Presented December 11, 2024.

Avoiding Chest Wall Irradiation After Mastectomy in Intermediate Risk 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 in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

Even though the use of postmastectomy radiotherapy has been widely accepted for patients with four or more positive lymph nodes, the role of postmastectomy radiotherapy for those with one to three positive nodes or node-negative disease remains controversial. Nonetheless, post mastectomy chest wall irradiation is commonly used to treat this intermediate risk group of breast cancer patients.

BIG 2-04 MRC SUPREMO trial is a Phase 3, randomized clinical study, conducted to investigate the impact of adjuvant chest wall irradiation (CWI) following mastectomy and axillary surgical staging among patients with operable breast cancer, at intermediate-risk of loco-regional recurrence. Intermediate risk breast cancer patients are those with 1-3 positive lymph nodes or patients who have no positive lymph nodes but whose cancers exhibit other factors that increase the risk of recurrence, such as grade 3 histology and/or lymphovascular invasion. Enrolled patients had breast tumors 5 cm or less (pT1–2) and 1-3 positive axillary lymph nodes (N1), breast tumors larger than 5 cm (pT3) and node-negative disease (N0), or breast tumors larger than 2 cm but no larger than 5 cm (pT2), N0 disease, and grade 3 histology and/or lymphovascular invasion.

Of the 1,607 eligible patients available for analysis 808 patients were randomly assigned to receive chest wall irradiation after mastectomy (chest wall irradiation group), and 799 patients were randomly assigned to omit chest wall irradiation after mastectomy (no chest wall irradiation group). Patients additionally received guideline-based axillary node clearance and systemic therapies. Chest wall Irradiation consisted of a total dose of 50 Gy in 25 daily fractions over 5 weeks or radiobiologically equivalent schedules including 40 Gy in 15 fractions over 3 weeks. Medial periclavicular/ internal mammary nodal irradiation was allowed but axillary irradiation was not permitted.

At a median follow up of 9.6 years, there were no significant differences in Overall Survival between those who received chest wall irradiation and those who did not (81.4% and 82.0%, respectively). Even though chest wall irradiation reduced the risk of chest wall recurrence by over half, the absolute rate of chest wall recurrence was reduced by less than 2%, which was clinically insignificant. Further, neither patients with N0 disease nor those with N1 disease experienced survival benefits with chest wall irradiation, suggesting that even patients with lymph node-positive disease could safely omit post-mastectomy chest wall irradiation.

It was concluded from the primary analysis of the SUPREMO trial that following mastectomy in patients with 1-3 positive nodes, or in node negative breast cancer patients with other risk factors treated with modern therapeutic interventions, chest wall irradiation has no impact on overall survival and has a clinically insignificant impact on chest wall recurrence.

GS2-03: Does postmastectomy radiotherapy in ‘intermediate-risk’ breast cancer impact overall survival? 10 year results of the BIG 2-04 MRC SUPREMO randomised trial: on behalf of the SUPREMO trial investigators. Presented at SABCS 2024; Presenting Author(s): Ian Kunkler; Abstract Number: SESS-3537

ENHERTU® after Endocrine Therapy in Advanced 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 in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 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 high levels of HER2 expression (IHC 3+ or 2+/FISH+) are classified as HER2-positive. 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. Tumors that are not classified as HER2-positive are classified as HER2-negative. Despite being classified as HER2-negative, majority these tumors still have some level of HER2 expression.

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. It is estimated that approximately 60-65% of HR-positive/HER2-negative breast cancers are HER2-low and potentially an additional 25% may be HER2-ultralow. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or chemotherapy. Resistance to hormonal therapy occurs in a majority of the patients and there is therefore an unmet need for agents with novel mechanisms of action. Further, there are no targeted therapies specifically approved for patients with HER2-low or HER2-ultralow expression, prior to chemotherapy.

ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA® (ado-Trastuzumab emtansine), another ADC targeting HER2, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, thus minimizing systemic exposure.

DESTINY-Breast06 is a global, randomized, open-label Phase III trial evaluating the efficacy and safety of ENHERTU® versus chemotherapy in patients with HR-positive, HER2-low, or HER2-ultralow advanced or metastatic breast cancer. This study enrolled 866 patients (N=713 for HER2-low and N=153 for HER2-ultralow). HER2-low was defined as IHC 1+ or 2+ or FISH negative and HER2-ultralow was defined as IHC 0 with membrane staining. Patients were randomized 1:1 to receive ENHERTU® 5.4 mg/kg every 3 weeks (N=436) or physicians choice of chemotherapy which included Capecitabine, Paclitaxel, or nab-Paclitaxel (N=430). Patients in the trial had no prior chemotherapy for advanced or metastatic disease and received at least two lines of prior endocrine therapy in the metastatic setting. Patients were also eligible if they had received one prior line of endocrine therapy combined with a CDK4/6 inhibitor in the metastatic setting and experienced disease progression within six months of starting 1st-line treatment, or received endocrine therapy as an adjuvant treatment and experienced disease recurrence within 24 months. Patients were stratified based on prior CDK4/6 inhibitor use, HER2 expression and prior taxane use in the non-metastatic setting. Patients in the trial had received a median of two prior lines of endocrine therapy. In the overall trial population, 14.9% of patients in the ENHERTU® group and 19.2% in the chemotherapy group had received one prior line of endocrine therapy. No patients had received prior chemotherapy for metastatic disease. The Primary endpoint was Progression Free Survival (PFS) in the HER2-low patient population as measured by Blinded Independent Central Review (BICR). Key Secondary endpoints included Progression Free Survival (PFS) in the overall trial population (HER2-low and HER2-ultralow), Overall survival (OS) in the HER2-low patient population, Objective Response Rate (ORR), Duration of response (DOR) and Safety. The median duration of follow-up was 18.2 months.

In the primary analysis of this study, results showed that in the HER2-low expression patients, ENHERTU® reduced the risk of disease progression or death by 38%, with a median PFS was 13.2 months in the ENHERTU® group, compared to 8.1 months for chemotherapy (HR=0.62; P<0.0001). For the overall trial population (HER2-low and HER2-ultralow), the median PFS results were similar and the median PFS was 13.2 months for ENHERTU® versus 8.1 months for chemotherapy (HR=0.63; P<0.0001). ENHERTU® reduced the risk of disease progression or death by 37% compared to chemotherapy.

A prespecified exploratory analysis showed that the improvement in PFS was consistent between patients with HER2-low and HER2-ultralow expression. In patients with HER2-ultralow expression, ENHERTU® reduced the risk of disease progression or death by 22% compared to chemotherapy, with a median PFS of 13.2 months versus 8.3 months, respectively (HR=0.78).

The Objective Response Rate (ORR) in HER2-Low Population was 56.5% for ENHERTU® compared to 32.2% for chemotherapy, in the Overall Trial Population was 57.3% for ENHERTU® versus 31.2% for chemotherapy, and in the HER2-Ultralow Subgroup was 61.8% for ENHERTU® versus 26.3% for chemotherapy. The median duration of response across these three groups was 14.3 months.

The safety profile of ENHERTU® was consistent with previous breast cancer clinical trials and no new safety concerns identified. The most common Grade 3 or higher treatment-related adverse events occurring in 5% or more of patients treated with ENHERTU® were neutropenia (20.7%) and anemia (5.8%). Interstitial Lung Disease (ILD), adjudicated as drug-related by an independent committee, occurred in 11.3% of patients treated with ENHERTU®. The majority of ILD events were low grade.

The results from the DESTINY-Breast06 trial underscore the significant clinical benefits of ENHERTU® in improving PFS and ORR in patients with HR-positive, HER2-low, and HER2-ultralow metastatic breast cancer, offering a promising alternative to standard chemotherapy. These findings highlight the potential of ENHERTU® to become a new standard of care for this patient population, pending further investigation and regulatory approval. The detailed positive outcomes underscore the clinical benefits and reinforce the promise of ENHERTU® in treating this challenging cancer subtype.

Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer. Bardia A, Hu X, Dent R, et al. for the DESTINY-Breast06 Trial Investigators. N Engl J Med 2024;391:2110-2122. DOI: 10.1056/NEJMoa2407086.

ITOVEBI® (Inavolisib)

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The FDA on October 10, 2024, approved ITOVEBI® with Palbociclib and Fulvestrant for adults with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, Human Epidermal growth-factor Receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy. ITOVEBI® is a product of Genentech, Inc.

Neoadjuvant Immunotherapy 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. The American Cancer Society estimates that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

Neoadjuvant chemotherapy is commonly used for patients with locally advanced Triple-Negative Breast Cancer (TNBC) and HER2-positive breast cancer. Alongside this standard treatment, there has been a push to develop new strategies aimed at increasing pathologic Complete Response (pCR) rates and improving survival outcomes. The introduction of Immune Checkpoint Inhibitors (ICIs) marked a major shift in cancer treatment, initially proving effective in melanoma and later showing promise in metastatic TNBC. This success led researchers to test ICIs in early-stage breast cancer as well.

Multiple randomized clinical trials have studied the impact of combining ICIs with chemotherapy in the neoadjuvant setting, some continuing ICI therapy as adjuvant treatment. These trials have gone beyond TNBC, exploring their use in other breast cancer subtypes like HER2-positive and Hormone Receptor-positive (HR-positive)/HER2-negative cancers. While some trials achieved their goals, the best way to integrate ICIs into early treatment remains debated, with concerns about cost and safety still under discussion.

In response to the need for clarity, a comprehensive systematic review and meta-analysis was conducted to assess the efficacy of neoadjuvant ICI therapy combined with chemotherapy in early-stage breast cancer. The analysis reviewed randomized controlled trials retrieved from the PubMed database up until December 2023. These trials focused on comparing ICIs plus chemotherapy versus chemotherapy alone in patients with early-stage breast cancer. The meta-analysis included 5114 patients from nine randomized controlled trials. These patients were subdivided into three major subgroups – TNBC (N=2097) patients, HR-positive/HER2-negative (N=1924) patients, and HER2-positive (N=1115) patients. The Primary outcomes evaluated were pathologic Complete Response (pCR) and Event-Free Survival (EFS) stratified by molecular phenotype and PD-L1 status. Secondary outcomes included incidence of Adverse Events (AEs), with a focus on immune-related toxicities.
The following are the Key Findings:
Pathologic Complete Response (pCR):
Triple-Negative Breast Cancer: Neoadjuvant ICIs improved the pCR rate significantly, with an increase from 46.6% to 59.9% (absolute improvement of 13.3%), regardless of PD-L1 status.
Hormone Receptor-Positive, HER2-Negative Tumors: There was a significant benefit of ICIs in PD-L1-positive tumors. The pCR rate increased from 14.8% to 24.6% in these cases (absolute improvement of 9.8%). However, there was no significant benefit in PD-L1-negative HR-positive/HER2-negative patients.
HER2-Positive Tumors: No significant pCR improvement was observed with the addition of ICIs in this subtype.

Event-Free Survival (EFS):
TNBC Patients with pCR: For those with TNBC who achieved a pCR, ICIs improved EFS (HR=0.65, 95% CI 0.42–1.00). The 5-year EFS was 92.0% for patients treated with ICIs compared to 88.0% without ICIs.
TNBC Patients with Residual Disease: ICIs also showed better EFS (HR=0.77, 95% CI 0.61–0.98) in patients who had residual disease after treatment, with a 5-year EFS of 63.3% compared to 56.1% without ICIs.
Adjuvant ICI in TNBC: No additional survival benefit was found with the use of adjuvant ICIs (after surgery) in TNBC patients, regardless of whether they achieved pCR or had residual disease.

Safety Profile:
Adverse Events (AEs): During neoadjuvant treatment, grade 3 or higher immune-related adverse events (AEs) were observed in 10.3% of patients treated with ICIs. The overall incidence of severe AEs (grade 3 or worse) was higher in ICI-treated patients (63.6%) compared to chemotherapy alone (54.1%). This reflects the toxicity costs associated with ICIs

Implications:
Neoadjuvant vs. Adjuvant ICI: The findings suggest that ICIs have greater efficacy when used in the neoadjuvant setting compared to adjuvant treatment. This is likely due to the tumor presence during neoadjuvant therapy, which allows for immune system priming through exposure to tumor antigens.
PD-L1 as a Biomarker: PD-L1 expression appears to be a more reliable biomarker of response to ICIs in HR-positive/HER2-negative tumors than in TNBC, where ICI benefit seems independent of PD-L1 status.
TNBC and Residual Disease: In patients with residual disease after neoadjuvant therapy, the benefit of continuing ICIs in the adjuvant setting is limited. This raises the question of whether continuing ICIs postoperatively is necessary or whether alternative strategies, like the use of other novel therapies, may be more effective.

In conclusion, Neoadjuvant Immune Checkpoint Inhibitors improve pathologic Complete Response rates and Event-Free Survival in early-stage breast cancer, especially in TNBC and PD-L1-positive HR-positive/HER2-negative tumors. However, their use in the adjuvant setting does not appear to provide added benefit. Ongoing trials, like the OptimICE-PCR trial, are designed to answer this question definitively by randomizing patients who achieve pCR to either continued ICI therapy or observation. For patients with residual disease post-neoadjuvant therapy, novel treatment approaches like Antibody-Drug Conjugates such as Sacituzumab Govitecan combined with ICIs are being investigated, offering potential new treatment paradigms.

Neoadjuvant Immune Checkpoint Inhibitors Plus Chemotherapy in Early Breast Cancer: A Systematic Review and Meta-Analysis. Villacampa G, Navarro V, Matikas A, et al. JAMA Oncol. 2024;10(10):1331-1341. doi:10.1001/jamaoncol.2024.3456.

ENHERTU® Effective Against Brain Metastases in Patients with HER2+ 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 in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 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 high levels of HER2 expression (IHC 3+ or 2+/FISH positive) are classified as HER2-positive. 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.

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 which result in a significantly worse prognosis compared to those without brain metastases. Local therapeutic interventions for brain metastases include neurosurgical resection and Stereotactic or Whole-Brain Radiation Therapy. However, CNS progression usually occurs within 6-12 months post-treatment. Furthermore, Whole-Brain Radiation Therapy, while commonly used for multiple brain metastases, is linked with cognitive decline, which is a particular concern for HER2+ breast cancer patients who can live several years after their diagnosis.

With regards to systemic treatment options for brain metastases, various other HER2-directed therapies have been explored including Tucatinib (TUKYSA®), which can cross the blood brain barrier. Tucatinib combined with Trastuzumab and Capecitabine is currently the preferred systemic treatment for HER2+ metastatic breast cancer patients with active brain metastases. The HER2CLIMB study investigated this combination in patients who had been previously treated. In patients with measurable brain metastasis at baseline, those receiving Tucatinib combined with Capecitabine, and Trastuzumab showed a confirmed intracranial Objective Response Rate (ORR) of 47.3%. CNS Progression-Free Survival (PFS) was 9.9 months for all patients and 9.6 months for those with active brain metastases.

Trastuzumab Deruxtecan-T-DXd (ENHERTU®) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). T-DXd has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike ado-Trastuzumab emtansine (KADCYLA®), another ADC targeting HER2, T-DXd has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, thus minimizing systemic exposure.

T-DXd has also shown promising intracranial activity in several studies, such as DESTINY-Breast01, 02, and 03, as well as the ongoing DESTINY-Breast07 and the DEBBRAH study, among others. These studies reported encouraging responses in patients with active brain metastases, suggesting potential efficacy in this difficult-to-treat population.

DESTINY-Breast12 is an open-label, multicentre, Phase IIIb/IV 2-cohort, non-comparative clinical trial designed to evaluate the efficacy and safety of T-DXd 5.4 mg/kg in patients with previously treated advanced/metastatic HER2-positive breast cancer. This study included two cohorts – patients without brain metastases (Cohort 1) and patients with brain metastases (Cohort 2), who have experienced disease progression following prior anti-HER2-based regimens and have received no more than two lines of therapy in the metastatic setting. Patients were enrolled into one of two cohorts according to the presence or absence of brain metastases at baseline. A total of 504 eligible patients (N=504) were enrolled across multiple sites of whom 263 patients had baseline brain metastases, and 241 patients had no baseline brain metastases. All patients received T-DXd 5.4 mg per kg every three weeks until disease progression or unacceptable toxicity occurred. Notably, patients with leptomeningeal metastases were excluded, as well as those who had received Tucatinib in prior treatments, to avoid confounding effects from a drug known to affect CNS lesions. The study allowed the inclusion of patients with stable or active brain metastases (previously treated and progressing), though it excluded those with no clinical indication for immediate retreatment of their brain metastases. Tumor assessments were performed regularly using MRI or CT scans. The Primary endpoint of Cohort 1 (non-brain metastases cohort) was Objective Response Rate (ORR) as assessed by Independent Review and the Primary endpoint of Cohort 2 (brain metastases cohort) was Progression-Free Survival (PFS). Additional endpoints included CNS PFS, CNS ORR, ORR in the brain metastases cohort and Safety.

Results showed a 12-month PFS rate of 61.6% for patients with brain metastases, with CNS-specific PFS of 58.9%. Those with stable brain metastases had a 12-month PFS of 62.9%, while patients with active brain metastases had a 12-month CNS PFS of 60.1%. For patients without brain metastases at baseline, the ORR was 62.7%, with a significant proportion achieving Partial or Complete Responses. A post-hoc analysis revealed a CNS ORR of 82.6% in patients with active brain metastases who had not undergone prior local CNS therapy and 50% in those who had progressed after prior local CNS treatments. Importantly, the safety profile of T-DXd was consistent with prior studies, though Interstitial Lung Disease (ILD) or pneumonitis occurred in approximately 13-16% of patients, with a small percentage experiencing Grade 5 (fatal) events.

In summary, the DESTINY-Breast12 study highlights the efficacy of Trastuzumab deruxtecan in treating HER2+ metastatic breast cancer, particularly in patients with brain metastases. These findings provide valuable insights into managing a challenging subset of breast cancer patients who often experience poor outcomes due to CNS progression. Further research is warranted to refine treatment strategies, especially for patients with ILD risk factors, and to explore potential combinatory regimens for long-term CNS control.

Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Harbeck, N., Ciruelos, E., Jerusalem, G. et al .for the the DESTINY-Breast12 study group. Nat Med (2024). https://doi.org/10.1038/s41591-024-03261-7

KISQALI® (Ribociclib)

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The FDA on September 17, 2024, approved KISQALI® with an Aromatase Inhibitor for the adjuvant treatment of adults with Hormone Receptor (HR)-positive, human Epidermal Growth Factor Receptor 2 (HER2)-negative Stage II and III early Breast cancer at high risk of recurrence. Additionally, FDA also approved the KISQALI® and FEMARA® Co-Pack for the same indication. KISQALI® and KISQALI® FEMARA® Co-Pack are products of Novartis Pharmaceuticals Corporation.

Late Breaking Abstract – ESMO 2024: Adjuvant KISQALI® Shows Deepening Benefit in 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. The American Cancer Society estimates that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 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 Hormone Receptor (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.

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. CDK4 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.

Ribociclib (KISQALI®) is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6, preferentially inhibiting CDK4 and blocking the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. The MONALEESA trials of Ribociclib have shown a consistent Overall Survival benefit, regardless of accompanying Endocrine Therapy, line of therapy, or menopausal status, in advanced breast cancer.

NATALEE is a global, multi-center, randomized, open-label Phase III trial, conducted to evaluate the efficacy and safety of Ribociclib with Endocrine Therapy as adjuvant treatment versus Endocrine Therapy alone, in patients with HR+/HER2-negative early breast cancer, who were at risk for disease recurrence. This study conducted in collaboration with Translational Research In Oncology (TRIO), randomly assigned 5,101 eligible men and pre- or postmenopausal women 1:1 to receive either adjuvant Ribociclib 400 mg orally daily for 3 years along with Endocrine Therapy consisting of Letrozole 2.5 mg/day or Anastrozole 1 mg/day, for 5 yrs or more (N= 2,549) or Endocrine Therapy alone for at least 5 years (N = 2,552). This study explored a lower Ribociclib starting dose of 400 mg daily rather than the dose approved for treatment in metastatic breast cancer (600 mg), with the goal to minimize toxicities and disruptions to patient quality of life, without compromising efficacy. Men and premenopausal women also received Goserelin. Eligible patients had an ECOG PS of 0-1 with Stage IIA (either N0 with additional risk factors or N1 with 1-3 axillary lymph nodes), Stage IIB, or Stage III HR-positive, HER2-negative breast cancer who were at risk for disease recurrence. Prior adjuvant Endocrine Therapy was allowed if initiated no more than 1 year before randomization. Stratification factors were menopausal status, disease stage, prior neoadjuvanr/adjuvant chemotherapy, and geographic region. Approximately 44% were premenopausal and 40% had Stage II breast cancer. Majority of patients (88%) received prior chemotherapy. The Primary endpoint of NATALEE was invasive Disease Free Survival (iDFS) as defined by the Standardized Definitions for Efficacy End Points (STEEP) criteria. Secondary endpoints included Distant Disease-Free Survival (DDFS) and Overall Survival (OS).

The authors had previously reported that at a median follow up of 34 months, the addition of Ribociclib to Endocrine Therapy significantly improved in invasive DFS compared with Endocrine Therapy alone (HR=0.748; P=0.0014), reducing the risk of disease recurrence by 25%.
The researchers in this updated analysis of the NATALEE trial presented the efficacy and safety data at data cutoff (29 Apr 2024), with all patients in the Ribociclib plus Endocrine Therapy group (N=2549) off treatment with Ribociclib. This update provided a robust framework for understanding the long-term implications of this therapeutic approach.

The updated analysis revealed that invasive DFS significantly favored the Ribociclib plus Endocrine Therapy combination over Endocrine Therapy alone. At the three-year mark, iDFS rates were 90.8% for the Ribociclib plus Endocrine Therapy group compared to 88.1% for those on Endocrine Therapy alone, with an absolute improvement of 2.7%. By the four-year follow-up, this gap widened, with iDFS rates of 88.5% versus 83.6%, reflecting a 4.9% absolute benefit. This benefit was consistent across various subgroups. Patients with node-negative disease (N0) experienced a 5.1% absolute increase in iDFS at four years, while those with node-positive disease (N+) saw a 5.0% improvement. Similarly, patients in Stage II had an absolute benefit of 4.3%, and those in Stage III achieved a 5.9% increase in their iDFS rates.

The Distant DFS data was similar to the iDFS findings, with Ribociclib plus Endocrine Therapy showing a Hazard Ratio of 0.715 (95% CI, 0.604–0.847; P<0.0001), indicating a substantial reduction in the risk of distant recurrence. While Overall Survival data remains immature, trends suggest a favorable outcome for the Ribociclib group.

Safety data revealed that Ribociclib was well tolerated, and remained consistent with previous analyses. The adverse events of special interest, particularly those Grade 3 or higher, included neutropenia (44.4%), liver-related issues (8.6%), and QT interval prolongation (1.0%).

The researchers concluded that in this 4-year landmark analysis, Ribociclib plus Endocrine Therapy reduced the risk of Invasive and Distant disease recurrence by 28.5% compared with Endocrine Therapy alone. Further, this benefit was maintained even after the end of planned 3-year Ribociclib treatment, for both node-positive and node-negative patients. This deepening efficacy, particularly evident in node-negative and high-risk early breast cancer patients, underscores the necessity of evolving treatment strategies in the fight against breast cancer.

Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (Pts) with HR+/HER2− early breast cancer (EBC): 4-year outcomes from the NATALEE trial. Fasching PA, Stroyakovskiy D, Yardley D, et al. DOI: 10.1016/j.annonc.2024.08.2251

Optimal Approach for Integrating Immune Checkpoint Inhibitors in Early-Stage Breast Cancer: A Meta-Analysis

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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. The American Cancer Society estimates that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

The integration of Immune Checkpoint Inhibitors (ICIs) into early-stage breast cancer treatment, particularly when combined with neoadjuvant chemotherapy, represents a significant advancement in oncology. Recent studies have explored combining ICIs with neoadjuvant chemotherapy to improve pathologic Complete Response (pCR) rates and survival outcomes. While ICIs have revolutionized treatment in metastatic settings, their role in early-stage breast cancer remains debated. This meta-analysis aims to evaluate the optimal approach for incorporating ICIs into early-stage breast cancer therapy by assessing their impact on pCR, Event-Free Survival (EFS), and safety profiles.

This study utilized the PubMed database, with a search conducted on December 10, 2023, to identify relevant randomized clinical trials (RCTs). Inclusion criteria focused on RCTs assessing the efficacy of neoadjuvant or adjuvant ICI plus chemotherapy in early-stage breast cancer. The studies had to provide data on pCR, EFS, and adverse events. Two independent reviewers extracted data from the selected RCTs. An individual patient data meta-analysis and a trial-level random-effect meta-analysis were conducted to synthesize findings. Nine RCTs involving 5114 patients were included. The population comprised 2097 patients with Triple-Negative Breast Cancer (TNBC), 1924 patients with Hormone Receptor–positive/HER2-negative (HR+/HER2-negative) tumors, and 1115 patients with HER2-positive tumors.

The Primary objectives of this study were to 1) Evaluate the association of neoadjuvant ICIs with pCR (defined as ypT0/is ypN0) across different molecular phenotypes of breast cancer 2) Quantify EFS assessed in patients with and without pCR and 3) Evaluate the severity of Adverse Events associated with ICIs including Grade 3 or higher immune-related Adverse Events (irAEs).

Efficacy of Neoadjuvant ICIs:
TNBC: Neoadjuvant ICIs led to a significant improvement in pCR rates, with an absolute increase of more than 10%. The efficacy was consistent across different PD-L1 expression statuses. Neoadjuvant ICIs also improved EFS for both patients achieving pCR (HR=0.65) and those with residual disease (HR=0.77). In patients with TNBC achieving a pCR, the addition of ICIs was associated with a 5-year EFS of 92.0% compared with 88.0% without them. In patients with residual disease, treatment with ICIs resulted in 5-year EFS of 63.3%, and 56.1% without them.
HR+/HER2-negative Tumors: ICIs improved pCR rates predominantly in the PD-L1+ subgroup, with an absolute increase of 12.2%. No significant benefit was observed in the PD-L1 negative subgroup or in HER2-positive tumors.

Adjuvant ICI Therapy:
No numerical improvement was observed with adjuvant ICI therapy, regardless of whether patients had achieved pCR or had residual disease. Hazard ratios were greater than 1, suggesting a lack of benefit.

The incidence of Grade 3 or higher irAEs during neoadjuvant therapy was 10.3%. This was consistent with known AEs of ICIs. Chemotherapy-related AEs, such as gastrointestinal and hematologic complications, was not significantly increased with ICI addition.

In conclusion, this meta-analysis indicates that neoadjuvant ICI therapy is beneficial in enhancing pCR rates and improving survival outcomes in early-stage TNBC and PD-L1+ HR+/HER2-negative tumors. The results suggest a preference for neoadjuvant over adjuvant ICI therapy, given the lack of benefit from adjuvant ICIs. Future research should focus on optimizing patient selection for neoadjuvant ICIs and exploring whether adjuvant therapy can be safely omitted, potentially reshaping treatment paradigms in early-stage breast cancer.

Neoadjuvant Immune Checkpoint Inhibitors Plus Chemotherapy in Early Breast Cancer: A Systematic Review and Meta-Analysis. Villacampa G, Navarro V, Matikas A, et al. JAMA Oncol. Published online August 29, 2024. doi:10.1001/jamaoncol.2024.3456.