Real-World Evaluation of Disease Progression After CDK 4/6 Inhibitor Therapy in Patients With Hormone Receptor-Positive Metastatic Breast Cancer.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDKi) have changed the landscape for treatment of patients with hormone receptor positive, human epidermal growth factor receptor 2-negative (HR+/HER-) metastatic breast cancer (MBC). However, next-line treatment strategies after CDKi progression are not yet optimized. We report here the impact of clinical and genomic factors on post-CDKi outcomes in a single institution cohort of HR+/HER2- patients with MBC. METHODS: We retrospectively reviewed the medical records of patients with HR+/HER2- MBC that received a CDKi between April 1, 2014 and December 1, 2019 at our institution. Data were summarized using descriptive statistics, the Kaplan-Meier method, and regression models. RESULTS: We identified 140 patients with HR+/HER2- MBC that received a CDKi. Eighty percent of patients discontinued treatment due to disease progression, with a median progression-free survival (PFS) of 6.0 months (95% CI, 5.0-7.1), whereas those that discontinued CDKi for other reasons had a PFS of 11.3 months (95% CI, 4.6-19.4) (hazard ratio (HR) 2.53, 95% CI, 1.50-4.26 [P = .001]). The 6-month cumulative incidence of post-CDKi progression or death was 51% for the 112 patients who progressed on CDKi. Patients harboring PTEN mutations pre-CDKi treatment had poorer clinical outcomes compared to those with wild-type PTEN. CONCLUSION: This study highlights post-CDKi outcomes and the need for further molecular characterization and novel therapies to improve treatments for patients with HR+/HER2- MBC

Phase Ib/II single-arm trial evaluating the combination of everolimus, lapatinib and capecitabine for the treatment of HER2-positive breast cancer with brain metastases (TRIO-US B-09).

BackgroundImproving outcomes for patients with human epidermal growth factor 2-positive (HER2+) central nervous system (CNS) metastases remains an unmet clinical need. This trial evaluated a novel combination of everolimus, lapatinib and capecitabine for this disease.MethodsPatients with trastuzumab-pretreated, HER2+ breast cancer brain metastasis without prior therapy with a mammalian target of rapamycin (mTOR) inhibitor were eligible. Patients received lapatinib and everolimus daily (continuously) and capecitabine twice daily (d1-14) in 21-d cycles. The primary endpoint was the 12-week CNS objective response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), best CNS ORR and extra-CNS ORR.ResultsA total of 19 participants were enrolled and treated with ⩾1 dose of the study drug. The median age was 58.5 years, the median number of therapies for metastatic breast cancer was 2.5 (0-11). Pretrial, 74% of participants had received prior lapatinib, capecitabine or both. A total of 63% had received previous CNS radiation or surgical resection and CNS radiation. The maximum tolerated doses were lapatinib at 1000 mg, everolimus at 10 mg, and capecitabine at 1000 mg/m2. Phase II proceeded with capecitabine at 750 mg/m2 due to better tolerability. The most common grade 3/4 adverse events were mucositis (16%), diarrhea, fatigue, and hypokalemia (11% each). Of 11 participants evaluable for 12-week CNS ORR, 3 (27%) had partial response and 7 (64%) had stable disease. The best CNS ORR in eligible participants was 28% (5/18). The median PFS and OS were 6.2 and 24.2 months, respectively.ConclusionsThis novel triplet combination of lapatinib, everolimus, and capecitabine is well tolerated and yielded a 27% response rate in the CNS at 12 weeks in heavily pretreated participants. Larger studies are warranted to further evaluate this regimen.Trial registrationClinicalTrials.gov: NCT01783756. Registered 05 February 2013, https://clinicaltrials.gov/ct2/show/NCT01783756

Phase Ib/II single-arm trial evaluating the combination of everolimus, lapatinib and capecitabine for the treatment of HER2-positive breast cancer with brain metastases (TRIO-US B-09)

Background: Improving outcomes for patients with human epidermal growth factor 2-positive (HER2+) central nervous system (CNS) metastases remains an unmet clinical need. This trial evaluated a novel combination of everolimus, lapatinib and capecitabine for this disease. Methods: Patients with trastuzumab-pretreated, HER2+ breast cancer brain metastasis without prior therapy with a mammalian target of rapamycin (mTOR) inhibitor were eligible. Patients received lapatinib and everolimus daily (continuously) and capecitabine twice daily (d1–14) in 21-d cycles. The primary endpoint was the 12-week CNS objective response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), best CNS ORR and extra-CNS ORR. Results: A total of 19 participants were enrolled and treated with ⩾1 dose of the study drug. The median age was 58.5 years, the median number of therapies for metastatic breast cancer was 2.5 (0–11). Pretrial, 74% of participants had received prior lapatinib, capecitabine or both. A total of 63% had received previous CNS radiation or surgical resection and CNS radiation. The maximum tolerated doses were lapatinib at 1000 mg, everolimus at 10 mg, and capecitabine at 1000 mg/m 2 . Phase II proceeded with capecitabine at 750 mg/m 2 due to better tolerability. The most common grade 3/4 adverse events were mucositis (16%), diarrhea, fatigue, and hypokalemia (11% each). Of 11 participants evaluable for 12-week CNS ORR, 3 (27%) had partial response and 7 (64%) had stable disease. The best CNS ORR in eligible participants was 28% (5/18). The median PFS and OS were 6.2 and 24.2 months, respectively. Conclusions: This novel triplet combination of lapatinib, everolimus, and capecitabine is well tolerated and yielded a 27% response rate in the CNS at 12 weeks in heavily pretreated participants. Larger studies are warranted to further evaluate this regimen. Trial registration: ClinicalTrials.gov: NCT01783756. Registered 05 February 2013, https://clinicaltrials.gov/ct2/show/NCT0178375