Clinical Value of Timely Targeted Therapy for Patients With Advanced Non-Small Cell Lung Cancer With Actionable Driver Oncogenes.

BACKGROUND: A recent real-world study observed that 24% of patients with advanced non-small cell lung cancer (aNSCLC) with actionable driver oncogenes (ADOs) initiated nontargeted therapies before biomarker test results became available. This study assessed the clinical impact of the timing of first-line (1L) targeted therapies (TTs) in aNSCLC. MATERIALS AND METHODS: This retrospective analysis of a nationwide electronic health record-derived deidentified database included patients aged ≥18 years diagnosed with aNSCLC with ADOs (ALK, BRAF, EGFR, RET, MET, ROS-1, and NTRK) from January 1, 2015, to October 18, 2022, by biomarker testing within 90 days after advanced diagnosis and received 1L treatment. Cohorts were defined by treatment patterns ≤42 days after test results: "Upfront TT" received 1L TT ≤42 days; "Switchers" initiated 1L non-TT before or after testing but switched to TT ≤42 days; and "Non-switchers" initiated non-TT before or after testing and did not switch at any time. Adjusted multivariate Cox regression evaluated real-world progression-free survival, real-world time to next treatment or death, and real-world overall survival. RESULTS: A total of 3540 patients met the study criteria; 78% were treated in a community setting, and 50% underwent next-generation sequencing (NGS). There was no significant difference in outcomes between Switchers and Upfront TT; inferior outcomes were observed in Non-switchers versus Upfront TT. CONCLUSION: Our findings demonstrated improved outcomes with upfront 1L TT versus non-TT in patients with aNSCLC with ADOs and observed timely switching to TT after biomarker test result had similar outcomes to Upfront TT. Opportunities remain to improve the use of NGS for early ADO identification and determination of 1L TT.

Results from a Real-World Multicenter Analysis of 482 Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib: A Look at Racial Differences.

BACKGROUND: Despite recent approvals of lifesaving treatments for chronic lymphocytic leukemia (CLL), real-world data on the tolerability of the Bruton tyrosine kinase inhibitor ibrutinib for CLL treatment are lacking, especially in Black patients. OBJECTIVE: To expand upon a previously reported retrospective chart review of ibrutinib-treated patients with CLL to increase the number of sites and the enrollment period in first-line (1L) and relapsed/refractory (R/R) settings with a subanalysis based on ethnicity. PATIENTS AND METHODS: Adults with CLL who initiated ibrutinib treatment from five centers were followed for ≥ 6 months. RESULTS: We identified 482 patients with CLL [405 White (153 1L, 252 R/R), 37 Black (17 1L, 20 R/R), 40 other/unidentified]. At baseline, 58.5% of all patients (68.8% of Black patients) had hypertension. At a median follow-up of 28.2 months, 31.1% of patients overall discontinued ibrutinib, 16.2% due to adverse events (12.2% 1L, 18.8% R/R). Overall, 46.0% of patients experienced ≥ 1 dose hold (40.2% 1L, 49.8% R/R), and 28.8% of patients experienced ≥ 1 dose reduction (24.9% 1L, 31.4% R/R). Among Black patients, ibrutinib was discontinued in 24.3% of patients (17.6% 1L, 30.0% R/R), 8.1% due to disease progression and 5.4% due to adverse events; 40.5% of patients experienced ≥ 1 dose hold (35.3% 1L, 45.0% R/R), and 32.4% of patients experienced ≥ 1 dose reduction (23.5% 1L, 40.0% R/R). CONCLUSIONS: Toxicity and disease progression were the most common reasons for ibrutinib discontinuations in the overall population and among Black patients, respectively. Encouraging research participation of underrepresented patient groups will help clinicians better understand treatment outcomes.

Ibrutinib, a Bruton tyrosine kinase inhibitor, is an approved oral targeted therapy for the treatment of chronic lymphocytic leukemia (CLL). Patients treated with ibrutinib can experience side effects (referred to as adverse events) and may need to reduce the drug dose (referred to as dose reductions) or stop treatment (referred to as discontinuations) for a variety of reasons. A previous study showed that patients who were treated with ibrutinib experienced frequent dose reductions and discontinuations. This study described dose reductions and discontinuations in a larger patient population treated with ibrutinib and also described outcomes in Black patients. Patients with CLL treated with ibrutinib were identified from five medical centers and were followed for a minimum of 6 months. Patients experienced frequent dose reductions and discontinuations in routine clinical practice. The most common cause of discontinuations was adverse events in the overall patient population and disease progression in the Black patient population. Black patients treated with ibrutinib had similar rates of dose reductions and discontinuations as the overall patient population. Rates of dose reductions and discontinuations for patients with CLL treated with ibrutinib were higher in this real-world study than in clinical trials.

Improving biomarker testing in advanced non-small-cell lung cancer and metastatic colorectal cancer: experience from a large community oncology network in the USA.

Aim: Biomarker testing detects actionable driver mutations to inform first-line treatment in advanced non-small-cell lung cancer (aNSCLC) and metastatic colorectal cancer (mCRC). This study evaluated biomarker testing in a nationwide database (NAT) versus the OneOncology (OneOnc) community network. Patients & methods: Patients with aNSCLC or mCRC with ≥1 biomarker test in a de-identified electronic health record-derived database were evaluated. OneOnc oncologists were surveyed. Results: Biomarker testing rates were high and comparable between OneOnc and NAT; next-generation sequencing (NGS) rates were higher at OneOnc. Patients with NGS versus other biomarker testing were more likely to receive targeted treatment. Operational challenges and insufficient tissue were barriers to NGS testing. Conclusion: Community cancer centers delivered personalized healthcare through biomarker testing.

What is this article about? Cancer therapies often work better in certain subgroups of patients. Tumors may have characteristics that can predict which therapies may be more likely to work. These cancer biomarkers may be identified by special testing, such as next-generation sequencing (NGS). If a biomarker is detected, the patient can potentially be treated with medicine that targets that biomarker. This study looked at biomarker testing of lung and colon cancers in two community cancer practices (OneOncology [OneOnc] and nationwide database [NAT]). What were the results? The biomarker testing rates were high (≥81%) and similar between OneOnc and NAT. NGS testing rates were higher at OneOnc than at NAT (58 vs 49% for non-small-cell lung cancer, 55 vs 42% for metastatic colorectal cancer [mCRC]), suggesting the success of OneOnc's networkwide educational, pathway and operational programs. NGS testing was lower in community practices due to operational challenges and insufficient tissue collection. Patients who had NGS versus other biomarker testing were more likely to receive treatment specifically for that biomarker. However, some patients started treatment before their biomarker results were reported, usually because of their disease and a long wait time for biomarker test results. What do the results of the study mean? Community cancer centers can treat patients with targeted medicine based on biomarker testing results. There are opportunities to increase the number of patients getting NGS testing, shorten turnaround times and reduce the number of patients who start treatment before getting their biomarker test results.

A Phase Ib, Open-label Study Evaluating the Safety and Efficacy of Ipatasertib plus Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer.

PURPOSE: To report the safety and efficacy of ipatasertib (AKT inhibitor) combined with rucaparib (PARP inhibitor) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with second-generation androgen receptor inhibitors. PATIENTS AND METHODS: In this two-part phase Ib trial (NCT03840200), patients with advanced prostate, breast, or ovarian cancer received ipatasertib (300 or 400 mg daily) plus rucaparib (400 or 600 mg twice daily) to assess safety and identify a recommended phase II dose (RP2D). A part 1 dose-escalation phase was followed by a part 2 dose-expansion phase in which only patients with mCRPC received the RP2D. The primary efficacy endpoint was prostate-specific antigen (PSA) response (≥50% reduction) in patients with mCRPC. Patients were not selected on the basis of tumor mutational status. RESULTS: Fifty-one patients were enrolled (part 1 = 21; part 2 = 30). Ipatasertib 400 mg daily plus rucaparib 400 mg twice daily was the selected RP2D, received by 37 patients with mCRPC. Grade 3/4 adverse events occurred in 46% (17/37) of patients, with one grade 4 adverse event (anemia, deemed related to rucaparib) and no deaths. Adverse events leading to treatment modification occurred in 70% (26/37). The PSA response rate was 26% (9/35), and the objective response rate per Response Criteria in Solid Tumors (RECIST) 1.1 was 10% (2/21). Median radiographic progression-free survival per Prostate Cancer Working Group 3 criteria was 5.8 months [95% confidence interval (CI), 4.0-8.1], and median overall survival was 13.3 months (95% CI, 10.9-not evaluable). CONCLUSIONS: Ipatasertib plus rucaparib was manageable with dose modification but did not demonstrate synergistic or additive antitumor activity in previously treated patients with mCRPC.

Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021).

BACKGROUND: Patients with metastatic castration-resistant prostate cancer have few treatment options after novel hormonal therapy (eg, abiraterone or enzalutamide). We aimed to evaluate cabozantinib, a tyrosine kinase inhibitor with immunomodulatory properties, in combination with the PD-L1 inhibitor atezolizumab in metastatic castration-resistant prostate cancer. METHODS: COSMIC-021 is an ongoing, multicentre, open-label, phase 1b study with a dose-escalation stage followed by tumour-specific expansion stages. Expansion cohort 6 in metastatic castration-resistant prostate cancer was enrolled at 42 cancer research centres in France, Italy, the Netherlands, Spain, and the USA. Eligible patients were aged 18 years or older and had metastatic castration-resistant prostate cancer with radiographic soft tissue progression following treatment with either enzalutamide or abiraterone, or both; measurable soft tissue disease per Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received oral cabozantinib 40 mg per day and intravenous atezolizumab 1200 mg once every 3 weeks. Study treatment continued until progressive disease or unacceptable toxicity. All enrolled patients were assessed for efficacy and safety. The primary endpoint was objective response rate per RECIST version 1.1 as assessed by the investigator. This study is registered with ClinicalTrials.gov, NCT03170960. FINDINGS: Between April 24, 2018, and Aug 31, 2020, 132 patients were enrolled and received at least one dose of study treatment. At data cutoff (Feb 19, 2021), median duration of follow-up was 15·2 months (IQR 9·6-21·7). Objective response rate was 23% (95% CI 17-32; 31 of 132 patients), with three (2%) confirmed complete responses and 28 (21%) confirmed partial responses. 72 (55%) of 132 patients had grade 3-4 treatment-related adverse events, with the most common being pulmonary embolism (11 [8%] patients), diarrhoea (nine [7%]), fatigue (nine [7%]), and hypertension (nine [7%]). There was one grade 5 treatment-related adverse event (dehydration). 74 (56%) of 132 patients had serious adverse events of any causality. 28 (21%) of 132 patients had treatment-related adverse events leading to discontinuation of either study drug. INTERPRETATION: Cabozantinib plus atezolizumab showed promising antitumour activity in patients with metastatic castration-resistant prostate cancer after novel hormonal therapy with an acceptable safety profile, supporting further evaluation of this combination. FUNDING: Exelixis.

Real-world ibrutinib dose reductions, holds and discontinuations in chronic lymphocytic leukemia.

Aim: A retrospective chart review of ibrutinib-treated patients with chronic lymphocytic leukemia (CLL) was conducted. Patients & methods: Adults with CLL who initiated ibrutinib were followed for ≥6 months (n = 180). Results: Twenty-five percent of first-line ibrutinib patients experienced ≥1 dose reduction, mainly due to adverse events (AEs; 79%). Treatment discontinuations and dose holds occurred in 20 and 34% of patients, respectively, most commonly due to AEs (73 and 74%). Approximately one-quarter of relapsed/refractory ibrutinib patients experienced ≥1 dose reduction, mainly due to AEs (88%). Treatment discontinuation and dose holds occurred in 40% of patients (58 and 76% due to AEs, respectively). Conclusion: Dose reductions, holds and discontinuations were frequent in patients with CLL receiving ibrutinib in routine clinical practice.

Lay abstract Chronic lymphocytic leukemia (CLL) is a cancer that develops from a type of white blood cells called 'B cells.' Ibrutinib is a targeted therapy that inhibits the activity of a protein called Bruton's tyrosine kinase, which plays a key role in CLL. Patients receiving ibrutinib treatment can experience side effects ('adverse events'). In addition, patients may need to reduce their drug dose ('dose reductions') or stop treatment ('discontinuations') for a variety of reasons. We reviewed patients' charts to describe dose reductions and discontinuations in ibrutinib-treated patients with CLL. Our results indicate that dose reductions and discontinuations were frequent in patients with CLL receiving ibrutinib in routine clinical practice, and that the most common reason was adverse events.

Prognostic Impact of Missed Chemotherapy Doses During Chemoradiation Therapy for Non-Small Cell Lung Cancer.

OBJECTIVE: The aim of this study is to investigate the impact of missed chemotherapy administrations (MCA) on the prognosis of non-small cell lung cancer (NSCLC) patients treated with definitive chemoradiation therapy (CRT). MATERIALS AND METHODS: In total, 97 patients with NSCLC treated with definitive CRT were assessed for MCA due to toxicities. Logistic regression was used to determine factors associated with MCA. Kaplan-Meier curves, log-rank tests, and Cox Proportional Hazards models were conducted. RESULTS: MCA occurred in 39% (n=38) of the patients. Median overall survival was 9.6 months for patients with MCA compared with 24.3 months for those receiving all doses (P=0.004). MCA due to decline in performance status was associated with the worst survival (4.6 mo) followed by allergic reaction (10.0 mo), hematologic toxicity (11 mo), and esophagitis (17.2 mo, P=0.027). In multivariate models, MCA was associated with higher mortality (hazard ratio, 1.97; P=0.01) and worse progression-free survival (hazard ratio, 1.96; P=0. 009). CONCLUSIONS: MCA correlated with worse prognosis and increased mortality. Methods to reduce toxicity may improve administration of all chemotherapy doses and increase overall survival in NSCLC treated with CRT.