CDK4/6 Inhibition in the Metastatic Setting: Where Are We Headed?

OPINION STATEMENT: Hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER-2-) metastatic breast cancer (MBC) is the most common subtype of breast cancer. Due to therapeutic advances with molecularly targeted therapies, the prognosis for patients with metastatic disease has improved significantly. The advent of CDK4/6 inhibitors (CDK4/6i) has changed the treatment paradigm for patients with HR+HER2-MBC. CDK4/6i allowed for marked improvement in overall survival, delaying the time to chemotherapy initiation, and improved quality of life for our patients. Efforts are now focused on the best approach(es) for patients after progression on CDK4/6i. Can we further harness the benefit of CDK4/6i in novel combinations at the time of progression? Should we continue CDK4/6i or proceed other novel agents or endocrine therapies? As we advance our treatment strategies for HR+HER2-MBC, there is no longer a one-size-fits-all model, but instead a multifaceted and personalized approach lending to improved outcomes for our patients.

Randomized Phase II Trial of Endocrine Therapy With or Without Ribociclib After Progression on Cyclin-Dependent Kinase 4/6 Inhibition in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: MAINTAIN Trial.

PURPOSE: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) improves progression-free survival (PFS) and overall survival (OS) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Although preclinical and clinical data demonstrate a benefit in changing ET and continuing a CDK4/6i at progression, no randomized prospective trials have evaluated this approach. METHODS: In this investigator-initiated, phase II, double-blind placebo-controlled trial in patients with HR+/HER2- MBC whose cancer progressed during ET and CDK4/6i, participants switched ET (fulvestrant or exemestane) from ET used pre-random assignment and randomly assigned 1:1 to the CDK4/6i ribociclib versus placebo. PFS was the primary end point, defined as time from random assignment to disease progression or death. Assuming a median PFS of 3.8 months with placebo, we had 80% power to detect a hazard ratio (HR) of 0.58 (corresponding to a median PFS of at least 6.5 months with ribociclib) with 120 patients randomly assigned using a one-sided log-rank test and significance level set at 2.5%. RESULTS: Of the 119 randomly assigned participants, 103 (86.5%) previously received palbociclib and 14 participants received ribociclib (11.7%). There was a statistically significant PFS improvement for patients randomly assigned to switched ET plus ribociclib (median, 5.29 months; 95% CI, 3.02 to 8.12 months) versus switched ET plus placebo (median, 2.76 months; 95% CI, 2.66 to 3.25 months) HR, 0.57 (95% CI, 0.39 to 0.85); P = .006. At 6 and 12 months, the PFS rate was 41.2% and 24.6% with ribociclib, respectively, compared with 23.9% and 7.4% with placebo. CONCLUSION: In this randomized trial, there was a significant PFS benefit for patients with HR+/HER2- MBC who switched ET and received ribociclib compared with placebo after previous CDK4/6i and different ET.

Trop-2 as a Therapeutic Target in Breast Cancer.

The emergence of Trop-2 as a therapeutic target has given rise to new treatment paradigms for the treatment of patients with advanced and metastatic breast cancer. Trop-2 is most highly expressed in triple negative breast cancer (TNBC), but the receptor is found across all breast cancer subtypes. With sacituzumab govitecan, the first FDA-approved, Trop-2 inhibitor, providing a survival benefit in patients with both metastatic TNBC and hormone receptor positive breast cancer, additional Trop-2 directed therapies are under investigation. Ongoing studies of combination regimens with immunotherapy, PARP inhibitors, and other targeted agents aim to further harness the effect of Trop-2 inhibition. Current investigations are also underway in the neoadjuvant and adjuvant setting to evaluate the therapeutic benefit of Trop-2 inhibition in patients with early stage disease. This review highlights the significant impact the discovery Trop-2 has had on our patients with heavily pretreated breast cancer, for whom few treatment options exist, and the future direction of novel Trop-2 targeted therapies.

Molecular Classification of Triple Negative Breast Cancer and the Emergence of Targeted Therapies.

Triple negative breast cancer (TNBC) represents 15% to 20% of all primary breast cancers and is the most aggressive subtype of breast cancer. There has been rapid progress in targeted therapy and biomarker development to identify the optimal treatments for TNBC. To update recent developments, this article comprehensively reviews molecular classification and biomarkers of TNBC and targeted therapy developments in immunotherapy, PARP and AKT pathway inhibitors, antibody-drug conjugates and androgen receptor blockade. The treatment of TNBC has dramatically evolved beyond basic cytotoxic chemotherapy into an expanding domain of targeted therapies tailored to the heterogeneity of this complex and aggressive disease. Progress will continue through the sustained and devoted efforts of our investigators and the patients who dedicatedly enroll in clinical trials. Through a daring persistence to challenge the status quo we now have the opportunity to offer our patients with TNBC a new sense of hope.

Safety and Efficacy of 7 Days on/7 Days off Versus 14 Days on/7 Days off Schedules of Capecitabine in Patients with Metastatic Colorectal Cancer: A Retrospective Review.

INTRODUCTION/BACKGROUND: The administration schedule of capecitabine for the treatment of metastatic colorectal cancer (mCRC) in clinical trials has been 14 days of drug with 7 days off in a 21 day cycle (14/7). In an effort to improve tolerability, an alternative every other week treatment (7/7) is often administered. The purpose of this study was to determine the safety and efficacy of administering 7/7 compared with 14/7 capecitabine dosing. MATERIALS AND METHODS: In this retrospective study, mCRC patients received capecitabine on a 7/7 or 14/7 schedule. The primary objective was to determine the tolerability of the respective dosing schedules, defined according to frequency of dose reductions and treatment delays. Secondary objectives included comparisons of objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety of dosing strategies. RESULTS: Of 175 included patients, 73 (41.7%) received the capecitabine 7/7 schedule and 102 (58.3%) received the 14/7 schedule. There was a statistically significant difference between the 7/7 and 14/7 groups with regard to dose reductions (4% vs. 29%; P < .001) and treatment delays (22% vs. 43%; P = .004). The incidence of any adverse effects (45% vs. 72%; P < .001) and specifically, palmar-plantar erythrodysesthesia (18% vs. 45%; P < .001), were significantly higher in the 14/7 group. No significant difference was seen with regard to ORR, PFS, or OS. CONCLUSION: Patients with mCRC who received the 7/7 schedule had significantly fewer dose reductions and treatment delays compared with patients who received the 14/7 schedule. Although no difference in efficacy outcomes were observed, prospective studies are needed to confirm these findings.

Two cancers in one: breast carcinoma with underlying melanoma.

A 61-year-old woman presented with a diagnosis of metastatic invasive lobular carcinoma of the right breast, and after treatment it had regressed or was stable except for a scalp nodule. When biopsied, the outer edges of the scalp lesion had findings consistent with breast carcinoma; however, the bulk of the tumor's pathology was consistent with melanoma. It appeared that most of the tumor was a highly vascularized melanoma with lobular breast carcinoma noted at its edges.