Treatment with fostamatinib in patients with immune thrombocytopenia: Experience from the Andalusian region in Spain-The Fostasur Study.

Immune thrombocytopenia (ITP) is characterized by low platelet counts (PLTs) and an increased risk of bleeding. Fostamatinib, a spleen tyrosine kinase inhibitor, has been approved as a second-line treatment for ITP. Real-world data on fostamatinib are lacking. This observational, retrospective, multicentre study, conducted in the Andalusia region of Spain, evaluated 44 adult primary ITP patients (47.7% female; median age 58 years; newly diagnosed ITP 6.8%; persistent 13.6%; chronic 79.5%; median four prior treatments) after ≥ 4 weeks of fostamatinib therapy. The median PLT at the initiation of fostamatinib was 15 × 109/L. Common reasons for starting fostamatinib were refractoriness or intolerance to prior therapy, oral medication preference, history of thrombosis and cardiovascular risk. Dosing was individualized based on efficacy and tolerance. After 2 weeks, global response rate was 56.8% (response and complete response). Response rates were 70.5%, 62.5% and 64% at 4 weeks, 12 weeks and at the end of the study respectively. Adverse events were mild, and no patients discontinued as a result. This real-world study demonstrated a response rate similar to fostamatinib as seen in the pivotal clinical trials while including newly diagnosed patients and allowing for individualized dosing.

[The Effect and Safety of Flumatinib in Patients with Chronic Myelogenous Leukemia Failed First-and Second-line Treatment].

OBJECTIVE: To analyze the efficacy and safety of flumatinib, a second-generation tyrosine kinase inhibitor (TKI) independently developed in China, in patients with chronic myelogenous leukemia in chronic phase (CML-CP) who falied first-line and second-line treatment. METHODS: The clinical data of 30 CML-CP patients treated with flumatinib in Lianyungang First People's Hospital from January 2020 to September 2022 were collected retrospectively. Among them, 15 patients who received imatinib first-line treatment but failed treatment were included in the second-line group, and the other 15 patients who failed second-line treatment with nilotinib or dasatinib were included in the third-line group. The hematological and molecular responses of the patients in the two groups at 3, 6 and 12 months of treatment, and the event-free survival (EFS) and adverse reactions of patients at the end of follow-up were statistical analyzed. RESULTS: At 3, 6, and 12 months of treatment, 10, 11, and 12 patients in the second line group achieved major molecular response (MMR), which was higher than that of 3, 4, and 5 patients in the third line group (P =0.010, P =0.011, P =0.010). At 3 months of treatment, 12 and 13 patients achieved complete hematological response (CHR) and early molecular response (EMR) in the second-line group, which was higher than that of 9 and 13 patients in the third-line group, but the difference between the two groups was not statistically significant (P =0.232, P =1.000); At 6 and 12 months of treatment, 6 and 7 patients in the second-line group achieved MR4.5, which were higher than of 3 and 2 cases in the third-line group, but the difference was not statistically significant (P =0.427, P =0.713). The hematological adverse reactions of patients in the second-line group during treatment the period were mainly grade 1-2 thrombocytopenia and anemia, and no grade 3-4 of adverse reactions occurred. In the third-line group, there were 2 cases of grade 1-2 thrombocytopenia, grade 1-2 anemia and white blood cell 3 cases were reduced each, 1 case of grade 3-4 anemia, 2 cases of grade 3-4 neutropenia. The non-hematological adverse reactions in the second-line group were rash (2 cases), headache (1 case), diarrhea (1 case), fatigue (1 case), limb pain (1 case). There were 1 cases of diarrhea, 1 cases of nausea, and 1 cases of edema in the third-line group. There was no statistical significance in hematological and non-hematological adverse reactions between the two groups of patients (P >0.05). At the end of follow-up, the EFS rate of patients in the second-line group was higher than that in the third-line group (100% vs 93.3%), but the difference was not statistically significant (P =0.317). CONCLUSION: The second-generation TKI flumatinib independently developed in China, has good curative effect and safety for CML-CP patients who failed first-line and second-line treatment.

Real-World Evidence of Ribociclib Plus Aromatase Inhibitors as First-Line Treatment in Advanced Breast Cancer: The BrasiLEEira Study.

PURPOSE: Cyclin inhibitors plus endocrine therapy represent the reference standard for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic breast cancer (ABC). Efficacy results on hard end points such as overall survival come from well-designed randomized clinical trials (RCTs). However, a limitation of RCTs is the low external results validity, and their extrapolation to a broader population may not be appropriate. Real-world studies can overcome these limitations, also increasing the reliability of RCTs. MATERIALS AND METHODS: The BrasiLEEira was an observational, longitudinal, retrospective, multicenter study to evaluate the effectiveness and safety of ribociclib plus nonsteroidal aromatase inhibitors in Brazilian women age 18 years or older with HR+/HER2- ABC. The study was approved by the institutional review boards of all 11 hospitals. Data were collected anonymously from medical records using an electronic case report form designed by an independent academic research organization, which conducted the study considering all recommendations of international guidelines. The primary end point was 1-year progression-free survival (PFS) rate. Secondary end points included mortality, dose reduction, and safety. RESULTS: The mean age of 76 patients was 57 years, and 28.9% were Black/Brown. The most prevalent comorbidity was arterial hypertension (34.7%). About 26.0% had endocrine-resistant disease, and 54.1% had more than three metastatic sites. The PFS rate was 77.6%. Three patients died (3.9%). Dose reductions occurred in 37.7% of patients. The most common adverse event was neutropenia (68.4%). CONCLUSION: The high-quality evidence from the BrasiLEEira study corroborates the RCTs' findings, expanding its validity to a broader spectrum and underrepresented population who may benefit from ribociclib treatment.

Predicting drug-drug interactions in breast cancer patients treated with CDK4/6 inhibitors and forward planning.

INTRODUCTION: Cyclin-dependent kinase (CDK) 4/6 inhibitors are cornerstones in the treatment of Hormone Receptor (HR) positive and Human Epidermal Growth factor (HER2) negative metastatic breast cancer. Given their widespread use in the metastatic setting and emerging use in the adjuvant setting, studying drug-drug interactions (DDI) of these medications is of utmost importance. AREAS COVERED: This review provides key background information on the CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib. We discuss drug-drug interactions including those with proton pump inhibitors as well as CYP3A substrates, inhibitors, and inducers. We describe the effect of these drugs on membrane transporters and their substrates as well as those drugs that increase risk of CDK4/6 toxicities. Finally, we explore future directions for strategies to minimize drug-drug interactions. EXPERT OPINION: It is crucial to be mindful of medications that may interfere with drug absorption, such as proton pump inhibitors, as well as those that interfere with drug metabolism, such as CYP3A4 inhibitors and inducers. Additionally, special consideration should be given to populations at higher risk for polypharmacy, such as older patients with greater comorbidities. These interactions and patient characteristics should be considered when developing individual treatment plans with CDK4/6 inhibitors.

Ribociclib plus Endocrine Therapy in Early Breast Cancer.

BACKGROUND: Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear. METHODS: In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy. RESULTS: As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P = 0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals. CONCLUSIONS: Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.).

A pragmatic guide for management of adverse events associated with lorlatinib.

Lorlatinib is a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). In clinical trials, lorlatinib has shown durable efficacy and a manageable safety profile in treatment-naive patients and in those who have experienced progression while receiving first- and/or second-generation ALK TKIs. Lorlatinib has a distinct safety profile from other ALK TKIs, including hyperlipidemia and central nervous system effects. Clinical trial data showed that most adverse events (AEs) can be managed effectively or reversed with dose modifications (such as dose interruptions or reductions) or with concomitant medications without compromising clinical efficacy or quality of life for patients. A pragmatic approach to managing AEs related to lorlatinib is required. We present patient-focused recommendations for the evaluation and management of select AEs associated with lorlatinib developed by clinicians and nurses with extensive lorlatinib expertise in routine clinical practice. The recommendations follow the general framework of "prepare, monitor, manage, reassess" to streamline AE management and assist in practical, actionable, and personalized patient care.

Cyclin-dependent kinase 4/6 inhibitors in the treatment of advanced or metastatic breast cancer.

OBJECTIVE: Despite the relatively high cure rates in early-stage breast cancer, advanced and metastatic breast cancer cases are associated with more inauspicious patient outcomes. Fortunately, with the advent of cyclin-dependent kinase (CDK)4/6 inhibitors (e.g. palbociclib, ribociclib, and abemaciclib) with endocrine therapy, survival in advanced and metastatic breast cancer has appreciably improved. In the current review, we discuss these distinctions and the concomitant implications associated with the individual CDK4/6 inhibitors. DATA SOURCES: We conducted an extensive PubMed search comprising several review articles on the topic of advanced or metastatic breast cancer treatment, with specific terms that included CDK4/6 inhibitors, treatment, and breast cancer. DATA SUMMARY: Palbociclib, ribociclib, and abemaciclib have exhibited superior progression-free survival differences compared to endocrine therapy alone. However, there are differences among the various CDK4/6 inhibitors with regard to overall survival, tolerability and quality of life. CONCLUSIONS: Ribociclib may be indicated for pre/perimenopausal patients, whereas abemaciclib is potentially recommended to address endocrine-resistant or visceral disease. Alternatively, palbociclib is associated with lower discontinuation rates than abemaciclib and unlike ribociclib, QTc prolongation is not observed with palbociclib.

A comparison between the adverse event profiles of patients receiving palbociclib and abemaciclib: analysis of two real-world databases.

BACKGROUND: Palbociclib and abemaciclib are cyclin-dependent kinase (CDK) 4/6 inhibitors currently used to treat breast cancer. Although their therapeutic efficacies are considered comparable, differences in adverse event (AE) profiles of the two drugs remain unclear. AIM: We analysed two real-world databases, the World Health Organization's VigiBase and the Food and Drug Administration Adverse Event Reporting System (FAERS), to identify differences in AE profiles of palbociclib and abemaciclib. METHOD: Data of patients with breast cancer receiving palbociclib or abemaciclib recorded until December 2022 were extracted from the VigiBase and FAERS databases. In total, 200 types of AEs were analysed. The reporting odds ratios were calculated using a disproportionality analysis. RESULTS: Cytopenia was frequently reported in patients receiving palbociclib, whereas interstitial lung disease and diarrhoea were frequently reported in those receiving abemaciclib. Moreover, psychiatric and nervous system disorders were more common in the palbociclib group, whereas renal and urinary disorders were more common in the abemaciclib group. CONCLUSION: This study is the first to show comprehensively the disparities in the AE profiles of palbociclib and abemaciclib. The findings highlight the importance of considering these differences when selecting a suitable CDK4/6 inhibitor to ensure safe and favourable outcomes for patients with breast cancer.

[Translated aticle] Topical and Oral Roflumilast in Dermatology: A Narrative Review.

Oral roflumilast is a phosphodiesterase-4 inhibitor approved for the prevention of exacerbations of chronic obstructive pulmonary disease and chronic bronchitis. In dermatology, topical roflumilast is authorized by the US Food and Drug Administration for the treatment of plaque psoriasis and mild to moderate seborrheic dermatitis. Several studies have described the off-label use of roflumilast in dermatology, including a randomized controlled trial showing its usefulness in the treatment of psoriasis; case reports and small series have also reported successful outcomes in hidradenitis suppurativa, recurrent oral aphthosis, nummular eczema, lichen planus, and Behçet disease. Roflumilast has a favorable safety profile, similar to that of apremilast, and it is considerably cheaper than new generation drugs and even some conventional immunosuppressants. We review the pharmacokinetics and pharmacodynamics of topical and oral roflumilast and discuss potential adverse effects and both approved and off-label uses in dermatology. Roflumilast is a promising agent to consider.

Use of Pharmacokinetic and Pharmacodynamic Data to Develop the CDK4/6 Inhibitor Ribociclib for Patients with Advanced Breast Cancer.

Ribociclib is an orally bioavailable, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. CDK4/6 inhibition by ribociclib leads to retinoblastoma tumor suppressor protein (Rb) reactivation, thereby restoring Rb-mediated cell cycle arrest. Ribociclib is approved for the treatment of patients with hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2-) advanced breast cancer (ABC), at the dose of 600 mg once daily (QD) during cycles of 21 days on/7 days off, with optional dose reduction to 400 mg and 200 mg. Ribociclib is rapidly absorbed with a median time to reach maximum plasma concentration of 2.4 h, mean half-life of 32.0 h and oral bioavailability of 65.8% at 600 mg. It is eliminated mainly by hepatic metabolism (~ 84% of total elimination), mostly by cytochrome P450 (CYP) 3A4. Age, body weight, race, baseline Eastern Cooperative Oncology Group status, food, mild hepatic impairment, mild-to-moderate renal impairment, proton pump inhibitors, and combination partners (non-steroidal aromatase inhibitors or fulvestrant) have no clinically relevant impact on ribociclib exposure. Ribociclib inhibits CYP3A at 600 mg leading to increased exposure of CYP3A substrates. Strong CYP3A inhibitors or inducers increase or decrease, respectively, ribociclib exposure. Exposure-safety and exposure-efficacy analyses support the clinical benefit of the 600 mg QD starting dose, with potential individualized dose reductions to 400 mg and 200 mg for effective management of the adverse events neutropenia and QTcF interval prolongation, while maintaining efficacy, in patients with HR+/HER2- ABC. Overall, these clinical pharmacology data informed ribociclib dose justification and clinical development, as well as its prescribing information for clinical use in advanced breast cancer patients.

Roflumilast foam 0.3% for adolescent and adult patients with seborrheic dermatitis: A randomized, double-blinded, vehicle-controlled, phase 3 trial.

BACKGROUND: The topical phosphodiesterase 4 inhibitor roflumilast has been studied in several dermatologic conditions. OBJECTIVE: Roflumilast foam 0.3% is being investigated as a topical treatment for seborrheic dermatitis (SD). METHODS: In this phase 3, double-blinded trial, patients with SD were randomly assigned (2:1 ratio) to once-daily roflumilast foam 0.3% or vehicle foam for 8 weeks. The primary efficacy outcome was Investigator Global Assessment (IGA) Success at week 8, defined as IGA of 0 (Clear) or 1 (Almost Clear) plus ≥2-point improvement from baseline. Safety was also assessed. RESULTS: 79.5% of roflumilast-treated and 58.0% of vehicle-treated patients met the primary endpoint (P < .001); statistically significant differences in IGA Success also favored roflumilast at week 2 (roflumilast: 43.0%; vehicle: 25.7%; P < .001) and week 4 (roflumilast: 73.1%; vehicle: 47.1%; P < .001). Roflumilast was well-tolerated with a low rate of treatment-emergent adverse events. LIMITATIONS: Study limitations include the 8-week treatment period for this chronic condition. CONCLUSIONS: Once-daily roflumilast foam was superior to vehicle in leading to IGA of Clear or Almost Clear plus ≥2-point improvement from baseline at 8 weeks in patients with SD. Longer trials are needed to determine durability and safety of roflumilast foam in SD.

Long-term patient-reported outcomes from monarchE: Abemaciclib plus endocrine therapy as adjuvant therapy for HR+, HER2-, node-positive, high-risk, early breast cancer.

BACKGROUND: In monarchE, abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile at 42-months median follow-up. With no expected disease-related symptoms, therapies in the adjuvant setting should preserve quality of life (QoL). With all patients off abemaciclib, we report updated patient-reported outcomes (PROs) for the full 2-year treatment period and follow-up. METHODS: Patients completed PROs including FACT-B, FACT-ES, and FACIT-Fatigue at baseline, 3, 6, 12, 18, and 24 months during treatment, and 1, 6, and 12 months after treatment discontinuation. Mixed effects repeated measures model estimated changes from baseline within and between arms for QoL scales and individual items. Meaningful changes were prespecified and no statistical testing was performed. Frequencies of responses to items associated with relevant adverse events and treatment bother were summarized. RESULTS: At baseline, completion rates for PRO instruments were >96 %. Mean changes from baseline for all QoL scales were numerically similar within and between arms (ie, less than prespecified thresholds). The same was observed for all individual items, except diarrhea. Within abemaciclib arm, meaningful differences for diarrhea were observed at 3 and 6 months (mean increases of 1.19 and 1.03 points on 5-point scale, respectively). During treatment, most patients in both arms (69-78 %) reported being bothered "a little bit" or "not at all" by side effects. Overall, patterns for fatigue were similar between arms. During post-treatment follow-up, PROs in both arms were similar to baseline. CONCLUSION: PRO findings confirm a tolerable and reversible toxicity profile for abemaciclib. QoL was preserved with the addition of adjuvant abemaciclib to endocrine therapy, supporting its use in patients with HR+, HER2-, high-risk early breast cancer.

Abemaciclib as adjuvant treatment for high-risk early breast cancer.

OBJECTIVE: To adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorization (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. METHOD: The efficacy and safety of abemaciclib were evaluated in a randomized, open-label, and multicenter phase III study. A total of 5637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive, and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1-3 positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3, or Ki-67≥20%. Patients were randomized (1:1) to receive adjuvant abemaciclib+endocrine therapy (n = 2808) or endocrine therapy alone (n = 2829) for 2 years, with endocrine therapy prescribed for at least 5 years. RESULTS: With a median follow-up of 15.5 months, abemaciclib+endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone [HR = 0.747 (95% CI 0.598-0.932), P = 0.0096]; achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3 years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%), and diarrhea (7.8% vs. 0.2%). CONCLUSIONS: The results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for high-risk early breast cancer in highly selected patients. However, in order to the efficacy results present less uncertainty, we must wait for a evaluation later, in which we can have a mature determination at 3 years (with more patients at risk).

Topical and Oral Roflumilast in Dermatology: A Narrative Review. / Roflumilast tópico y oral en dermatología. Una revisión narrativa.

Oral roflumilast is a phosphodiesterase-4 inhibitor approved for the prevention of exacerbations of chronic obstructive pulmonary disease and chronic bronchitis. In dermatology, topical roflumilast is authorized by the US Food and Drug Administration for the treatment of plaque psoriasis and mild to moderate seborrheic dermatitis. Several studies have described the off-label use of roflumilast in dermatology, including a randomized controlled trial showing its usefulness in the treatment of psoriasis; case reports and small series have also reported successful outcomes in hidradenitis suppurativa, recurrent oral aphthosis, nummular eczema, lichen planus, and Behçet disease. Roflumilast has a favorable safety profile, similar to that of apremilast, and it is considerably cheaper than new generation drugs and even some conventional immunosuppressants. We review the pharmacokinetics and pharmacodynamics of topical and oral roflumilast and discuss potential adverse effects and both approved and off-label uses in dermatology. Roflumilast is a promising agent to consider.

Liver toxicity with ribociclib in a patient with metastatic hormone receptor positive postmenopausal breast cancer.

INTRODUCTION: In recent years, highly selective reversible CDK4/6 inhibitors have been combined with aromatase inhibitors for their efficacy and ease of application in the treatment of advanced stage of hormone-responsive breast cancers. Oral use of these drugs facilitates patient compliance. However, adverse drug reactions are reported due to these drugs, in the literature. Diverse adverse reactions such as skin reactions, liver toxicity, and vitiligo with ribociclib have been reported. CASE REPORT: In this study, we present of liver toxicity due to the use of ribociclib in a case of advanced breast cancer with metastases. It is noteworthy that the patient did not have any other concomitant disease and did not take any other medication. MANAGEMENT AND OUTCOME: After the 600 mg initial dose of ribociclib, neutropenia occurred at the beginning of the therapy, the dose was reduced to 400 mg, and liver enzymes started to rise in the second month of the therapy. In the fifth month of the intermittent treatment period, liver toxicity was grade 3. DISCUSSION: Liver adverse reaction occurred due to ribociclib use in the patient who had no history of any other disease. The Naranjo algorithm score was evaluated as 9. Considering the excretion of ribociclib by sulfation, cysteine conjugation, and glucuronidation, which are phase II reactions, n-acetyl cysteine (NAC) treatment (600 mg/day) was started for the patient. NAC therapy is recommended to reduce elevated liver enzymes in the case. The patient's treatment has been continuing with palbociclib for 5 months. No increase in liver enzymes was observed.

Abemaciclib as adjuvant treatment for high-risk early breast cancer. / [Artículo traducido] Abemaciclib en adyuvancia para el tratamiento del cáncer de mama precoz de alto riesgo.

OBJECTIVE: To adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorisation (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. METHOD: The efficacy and safety of abemaciclib were evaluated in a randomized, open-label and multicenter phase III study. A total of 5,637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1-3positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3 or Ki-67 ≥ 20%. Patients were randomized (1:1) to receive adjuvant abemaciclib + endocrine therapy (n = 2,808) or endocrine therapy alone (n = 2,829) for 2 years, with endocrine therapy prescribed for at least 5 years. RESULTS: With a median follow-up of 15.5 months, abemaciclib + endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone (HR = 0.747 [95% CI 0.598-0.932], p = 0.0096); achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3-years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%) and diarrhea (7.8% vs. 0.2%). CONCLUSIONS: The results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for high-risk early breast cancer in highly selected patients. However, in order to the efficacy results present less uncertainty, we must wait for a evaluation later, in which we can have a mature determination at 3 years (with more patients at risk).

Efficacy, safety, and prognosis prediction in patients treated with ribociclib in combination with letrozole: Final results of phase 3b RIBECCA study in hormone receptor positive, human epidermal growth factor receptor-2 negative, locally advanced or metastatic breast cancer.

BACKGROUND: In MONALEESA-2, addition of ribociclib to letrozole resulted in significantly longer progression-free survival (PFS) in postmenopausal women with HR+HER2- advanced breast cancer (ABC). RIBociclib for the treatment of advanCed breast CAncer (RIBECCA) study investigated ribociclib plus letrozole in a patient population reflecting routine clinical practice. PATIENTS AND METHODS: In this multicenter, open-label, single-arm, phase 3b study, patients with HR+HER2- ABC not amenable to curative therapy and ECOG performance status ≤ 2 received ribociclib plus letrozole (cohort A: postmenopausal women and men in first-line; cohort B: pre-/perimenopausal women in first-line [B1], patients pretreated for advanced disease [B2]). The primary endpoint was clinical benefit rate (CBR) by week 24; secondary endpoints included overall response rate (ORR), PFS, overall survival (OS), and safety. Association of patient and tumor characteristics with PFS was analyzed by multivariable Cox regression analysis. RESULTS: Overall, 487 patients were evaluable for efficacy, 502 for safety. By week 24, CBR was 60.8 % (95 % CI, 56.3-65.1), ORR was 19.3 % (95 % CI, 15.9-23.1). Median PFS was 21.8 months (95 % CI, 13.9-25.3) in first-line postmenopausal patients and 11.0 months (95 % CI, 8.2-16.4) in premenopausal and pretreated patients. Median OS was not reached. Higher baseline ECOG performance status, higher histological grade, and negative progesterone receptor status showed an unfavorable effect on PFS. Most common adverse events were neutropenia (50.0 %), nausea (42.0 %), and fatigue (39.2 %). CONCLUSION: In this broad population of patients with HR+HER2- ABC, efficacy and safety results of ribociclib plus letrozole were similar to those observed in pivotal trials.

In-depth Analysis of Lorlatinib-related neurocognitive Adverse Events in Patients With Non-small-cell Lung Cancer.

INTRODUCTION: Lorlatinib is a potent, brain penetrant, next-generation ALK/ROS1 TKI, with high response rates and durable responses, including the brain. However, a significant drawback is the manifestation of neurocognitive adverse events (NCAEs). Despite being generally low-grade in severity, these NCAEs can be physically and mentally disabling. Extensive neurocognitive testing in this group of patients is lacking; therefore we conducted this study. PATIENTS AND METHODS: This observational prospective study was conducted across 3 Dutch university hospitals. Patients with metastatic NSCLC with an ALK- or ROS1-rearrangement and having an indication to start lorlatinib in daily clinical practice were eligible. The primary endpoints were to identify changes in neurocognitive functioning, measured through neurocognitive assessment at intervals of 2 weeks and 2 months after starting lorlatinib, in comparison to baseline. As a secondary endpoint, the correlation between neurocognitive impairment and self-reported neurocognitive dysfunction was examined. RESULTS: Between June 2019 and October 2022, 22 patients were included. Among the various neurocognitive tests administered, only the Hopkins Verbal Learning Test-Revised parts b and c demonstrated a significant and clinically relevant decrease in scoring 2 weeks post initiation of lorlatinib (P = .036 and P = .003, respectively). However, these returned to baseline at the 2-month evaluation. The questionnaires did not result in significantly different outcomes over time. CONCLUSION: Lorlatinib treatment did not result in a sustained and significant decline within any of the specified neurocognitive domains.