Progression after First-Line Cyclin-Dependent Kinase 4/6 Inhibitor Treatment: Analysis of Molecular Mechanisms and Clinical Data.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6iss) are widely used in first-line metastatic breast cancer. For patients with progression under CDK4/6is, there is currently no standard treatment recommended at the category 1 level in international guidelines. The purpose of this article is to review the cellular mechanisms underlying the resistance to CDK4/6is, as well as treatment strategies and the clinical data about the efficacy of subsequent treatments after CDK4/6is-based therapy. In the first part, this review mainly discusses cell-cycle-specific and cell-cycle-non-specific resistance to CDK4/6is, with a focus on early and late progression. In the second part, this review analyzes potential therapeutic approaches and the available clinical data on them: switching to other CDK4/6is, to another single hormonal therapy, to other target therapies (PI3K, mTOR and AKT) and to chemotherapy.

The role of mean corpuscular volume and red cell distribution width in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors: the MARECAP retrospective study.

Background: Tyrosine-kinase inhibitors (TKIs) and immunotherapy represent the backbone treatment for metastatic renal cell carcinoma (mRCC) patients. The aim of the present study was to describe mean corpuscular volume (MCV) and red cell distribution width (RDW) in mRCC patients treated with pazopanib or cabozantinib, and to explore their potential impact on oncological outcomes. Materials and methods: We conducted a multicenter retrospective observational study in mRCC patients treated with pazopanib or cabozantinib between January 2012 and December 2020 in nine Italian centers. Descriptive statistics, univariate, and multivariate analyses were performed. Objectives: The primary endpoints were the incidence and trend over time of anemia, macrocytosis (elevated MCV), and anisocytosis (elevated RDW). The secondary endpoints were the correlations of MCV and RDW with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: A total of 301 patients were enrolled; mean Hb value was 12.5 g/dl, a mean increase of 1 g/dl was observed at day 15 and maintained at 3 months. Most patients had baseline macrocytosis (MCV levels > 87 fl), with a significant mean increase after 3 months of treatment. At univariate analysis patients with macrocytosis had better ORR, longer PFS, and OS. About one third of patients had baseline anisocytosis (RDW > 16%), with a significant mean increase after 3 months of treatment. At univariate analysis, patients with RDW values ⩽ 16% had higher ORR, longer PFS, and OS. At multivariate analysis, baseline macrocytosis was significantly associated with better PFS in patients treated with pazopanib and baseline anisocytosis with shorter OS in all patients. Conclusions: mRCC patients treated with pazopanib or cabozantinib may have baseline macrocytosis and anisocytosis. A significant increase of Hb, MCV, and RDW after TKIs start was observed. Baseline macrocytosis is positively correlated with PFS in patients treated with pazopanib and baseline anisocytosis affects survival of patients treated with TKIs.

Tailoring treatment with cabozantinib or pazopanib in patients with metastatic renal cell carcinoma: does it affect outcome?

BACKGROUND: Metastatic renal cell carcinoma (mRCC) treatment is still largely based on TKI use. Treatment adjustment due to toxicities is often needed. The aim of the present study was to determine the impact of treatment modifications on the outcome of mRCC patients treated with cabozantinib or pazopanib. RESEARCH DESIGN AND METHODS: This retrospective multicenter study enrolled consecutive patients receiving cabozantinib or pazopanib between January 2012 and December 2020. We evaluated the correlation of TKI treatment modifications with grade 3-4 toxicities and progression-free (PFS) and overall survival (OS). We also performed a landmark analysis excluding patients who did not undergo at least 5 months of therapy. RESULTS: Among 301 patients, 179 (59%) were treated with pazopanib, 122 (41%) with cabozantinib. Treatment modifications were related to grade 3-4 toxicities (p < 0.0001). We observed a statistically significant longer PFS and OS in patients who underwent dose reductions (p < 0.0001 for both PFS and OS), temporary interruption (p < 0.0001 for both PFS and OS) and schedule modifications (p = 0.007 for PFS and p = 0.012 for OS) at univariate analysis. These results were confirmed at multivariable and landmark analyses. CONCLUSIONS: Tailoring treatment with pazopanib and cabozantinib was associated with better PFS/OS.

The impact of proton-pump inhibitors administered with tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma.

Tyrosine kinase inhibitors (TKIs) are the backbone of the systemic treatment for patients with metastatic renal cell carcinoma (mRCC). TKIs such as pazopanib and cabozantinib can interact with other drugs concomitantly administered, particularly with proton-pump inhibitors (PPIs), possibly impacting the effectiveness of the anticancer treatment and patients outcome. Few data are available about this interaction. We conducted a multicenter retrospective observational data collection of patients with mRCC treated with pazopanib or cabozantinib between January 2012 and December 2020 in nine Italian centers. Univariate and multivariate analyses were performed. The aim was to describe the impact of baseline concomitant PPIs on the outcome of patients to pazopanib and cabozantinib in terms of response, progression-free survival (PFS) and overall survival (OS), toxicity, and treatment compliance. The use of PPI in our study population (301 patients) significantly influenced the effectiveness of TKIs with worse PFS (16.3 vs. 9.9 months; P < 0.001) and OS (30.6 vs. 18.4 months; P = 0.013) in patients taking PPI at TKI initiation. This detrimental effect was maintained both in the pazopanib and cabozantinib groups. The use of PPI influenced the toxicity and TKI treatment compliance with a reduction of dose or schedule modifications, and treatment interruptions in the population taking PPIs. Our study demonstrates that the use of PPIs can significantly influence the outcome and compliance of patients with mRCC to TKI treatment, suggesting the importance of a more careful selection of patients who need a gastroprotective therapy, avoiding indiscriminate use of PPIs.