Clinical Outcomes of Patients with HER2 Positive Metastatic Breast Cancer to the Brain, with First-Line Trastuzumab, Pertuzumab and Chemotherapy, in a Real-World Setting.

Background: In this observational study, we analyzed the treatment patterns and clinical outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) who developed brain metastases during their disease in a 2.7 million-member public health-provider in Israel. Methods: Newly diagnosed patients with mBC who initiated first-line treatment between January 2013 and June 2021 were identified. Time on treatment (ToT) and overall survival (OS) were assessed at a minimum of 6 months follow-up (cutoff: December 2021). Results: We identified a total of 61 patients: 98.4% females, median age 50 years (IQR = 44-63), 85% invasive ductal tumors, 44% hormone receptor positive, 51% performance status 0-1. The median duration of follow-up was 6.2 years. All patients initiated a combination treatment of trastuzumab, pertuzumab, and chemotherapy (TPC), and 72% moved to second-line treatment during the study follow-up period (82% ado-trastuzumab emtansine). The median ToT for first-line and second-line treatments were 16.9 months (95% CI = 13.9-27.7) and 7.9 months (95% CI = 5.6-10.9), respectively. The median overall survival (OS) was 45.5 months (95% CI = 35.4-71.2) from the initiation of first-line treatment. When considering the timing of brain metastases, the median OS was 36.3 months (95% CI = 10.0-NR) for those diagnosed upfront (n = 15, 25%), 59.1 months (95% CI = 32.5-NR) for those diagnosed while on TPC (n = 25, 41%), and 40.8 months (95% CI = 35.4-NR) for those diagnosed at a later stage (n = 21, 34%). The median OS from brain metastases diagnosis was 25.1 months (95% CI = 17.0-34.6). Conclusion: Patients with upfront brain involvement at the time of mBC diagnosis had shorter survival compared to those who started TPC without brain metastases. Nonetheless, the overall results from this study compare favorably with previous studies and contribute to understanding the value of traditional treatment options, which will serve as a baseline for future treatment strategies in the real-world setting.

Time on Treatment and Survival Outcomes for Patients Treated With First-line Osimertinib vs. Other Tyrosine Kinase Inhibitors, for EGFR Mutation-positive Metastatic Non-small Cell Lung Cancer: Real-world Experience Data.

BACKGROUND/AIM: In this observational study, we analyzed the time on treatment (ToT) and overall survival (OS) of patients with metastatic non-small cell lung cancer (mNSCLC) in a 2.7-million-member public health provider in Israel. PATIENTS AND METHODS: Newly diagnosed patients with mNSCLC who initiated first-line tyrosine kinase inhibitor (TKI) therapy between Jan 2017-Dec 2020 were identified from the National Cancer Registry and Maccabi Healthcare Services database. Outcomes were assessed at a minimum of 23 months of follow-up (cutoff: 30th November 2022). All analyses compared first-line treatment osimertinib vs. standard TKIs (erlotinib, afatanib or gefitinib). RESULTS: A total of 165 patients (59% female, median age 68 years) were identified, including 58% smokers, 95% with adenocarcinomas, 33% with brain metastases, and 62%/15%/23% with 0-1/2-4/unknown performance status (PS). Of these, 77 (47%) were treated with standard TKI drugs and 88 (53%) with osimertinib as first-line treatment. The median duration of follow-up was 33.6 months (95%CI=29.9-37.3) and 58.5 months (95%CI=52.5-64.4) for patients who received osimertinib and standard TKIs, respectively. The median ToT (in months) was significantly (p<0.0001) longer with osimertinib (17.6; 95%CI=13.71-23.9) vs. standard TKIs (9.40; 95%CI=7.17-12.1). The 24-month survival rate was 58.0% among patients who received osimertinib and 50.6% among those who received standard TKI therapy (p=0.18). From second-line treatment initiation, 43.8% of those who received second-line osimertinib and 17.7% of those that received other second-line treatment were still alive at 24 months. CONCLUSION: Compared to standard TKIs, first-line osimertinib treatment was associated with a significantly longer ToT, and a longer OS. Our cohort also included patients with PS 2-4 who would not necessarily be included in clinical trials, allowing analysis of a real-world population.

Real-world outcomes of patients with metastatic endocrine-responsive breast cancer receiving palbociclib-based combinations.

Aim: To describe treatment journey and clinical outcomes after palbociclib initiation in HR+/HER2- breast cancer patients across multiple lines. Materials & methods: Adult patients (n = 559) were identified in a population-based study between January 2018 and June 2020. Results: Median follow-up time was 41.2 months. The starting dose was 125 mg for more than 85% of patients, and a third had dose reduction. Median time on treatment was 30.5 months for palbociclib + aromatase inhibitors for patients that received first-line treatment after metastatic diagnosis, and 12.6 months for palbociclib + fulvestrant across multiple lines, and longer for patients that had a dose reduction during treatment. At 48 months, 59.3 and 27.3% of patients were still alive, respectively. Subsequent lines resulted in median time on treatment of 4.4-7.7 months in both groups. Conclusion: Time on treatment for palbociclib was comparable to data from clinical trials, and follow-up allowed us to examine subsequent treatment after initial treatment failure. Dose reduction was common in the real-world setting and did not adversely affect efficacy.

We used healthcare data from Israel to study the outcomes of adults (mostly women) who had breast cancer that spread (metastatic) and who started treatment with anticancer medications in the form of palbociclib in combination with either aromatase inhibitors (as first treatment after metastatic disease diagnosis) or fulvestrant (after having been treated with a different medication) between January 2018 and June 2020. Patients treated with palbociclib with aromatase inhibitors (52%) were on average 63 years old, and most had medium to high socioeconomic status (63%) and functioned independently (60%). Patients were treated on average for 30.5 months, and just over a third switched to a different treatment after their disease worsened. Four years after starting treatment, 59% of patients were still alive. Patients treated with palbociclib and fulvestrant, after having been treated with a different medication (48%), were on average 66 years old, and 61% had medium to high socioeconomic status and 50% functioned independently. These patients were treated on average for 12.6 months, and over two-thirds switched to a new treatment. Four years after starting this treatment, 27% of patients were still alive. Overall, most patients included in this study started treatment with the recommended dose of palbociclib (125 mg), and a third had to change to a lower dose to continue treatment (probably due to side effects). Clinical trial registration: NCT04671615 (ClinicalTrials.gov).

Association between diabetes mellitus and reduced efficacy of pembrolizumab in non-small cell lung cancer.

BACKGROUND: Diabetes mellitus (DM) is a highly prevalent chronic metabolic disorder. Although DM has been associated with immune dysfunction, the effect of DM on the efficacy of immunotherapy is unknown. This study aimed to evaluate the impact of DM on the efficacy of pembrolizumab in metastatic non-small cell lung cancer (NSCLC). METHODS: The authors reviewed the medical records of consecutive metastatic NSCLC patients treated with first-line pembrolizumab either alone or in combination with chemotherapy at a single tertiary center. For validation, a computerized data from Maccabi Healthcare Services, a 2.5-million-member state health service was used. RESULTS: Of the 203 eligible patients, 51 (25%) had DM. Patients with DM had a significantly shorter median progression-free survival (PFS) (5.9 vs. 7.1 months, p = .004) and overall survival (OS) (12 vs. 21 months, p = .006). The shorter OS in diabetic patients was more pronounced when pembrolizumab was given alone (12 vs. 27 months, p = .03) than when combined with chemotherapy (14.3 vs. 19.4 months, p = .06). Multivariate analysis confirmed DM as an independent risk factor for shorter PFS (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.11-2.50, p = .01) and OS (HR, 1.73; 95% CI, 1.09-2.76, p = .02). In a validation cohort of 452 metastatic NSCLC patients, the time on pembrolizumab treatment was shorter in diabetic patients (p = .025), with only 19.6% of patients remaining on treatment at 12 months compared to 31.7% of the nondiabetic patients. CONCLUSIONS: This study suggests immunotherapy is less beneficial in diabetic NSCLC patients. More work is needed to verify our findings and explore similar effects in other cancer entities.

The reimbursement process in three national healthcare systems: variation in time to reimbursement of pembrolizumab for metastatic non-small cell lung cancer.

In this article, we focus on the reimbursement process, and as an example, characterize the time to reimbursement of pembrolizumab, a PD-1 immune checkpoint inhibitor for treatment of metastatic NSCLC from publicly available websites, in three different healthcare systems: The National Institute for Health and Care Excellence (NICE) in the UK, the Pharmaceutical Benefits Advisory Committee (PBAC) in Australia, and the National Advisory Committee for the Basket of Health Services in Israel, all who have publicly funded health systems which include drug coverage. Our study found that there are substantial differences in time to reimbursement of pembrolizumab for the same conditions in different countries, with NICE and The National Advisory Committee for the Basket of Health Services in Israel approving one condition at the same time, Israel approving two conditions earlier than NICE, and PBAC lagging behind for every condition. These differences could be due to the differences in health policy systems and the many factors that affect reimbursement. Comparing the reimbursement process between different countries can highlight the challenges facing their health systems in early adoption of new treatments.

Predictors of treatment initiation and mapping the cancer diagnostic pathway: A retrospective observational cohort study of patients with metastatic non-small cell lung cancer.

BACKGROUND: Health-care providers in the US revealed that a substantial proportion of mNSCLC patients do not receive any first-line therapy and the biggest gaps in care are time inefficiencies in the diagnostic process. The goal of this study was to determine whether such gaps are found in Israel where healthcare is universal and participation in a medical insurance plan is free and compulsory. METHODS: We conducted a retrospective, observational cohort study using the computerized data of Maccabi Healthcare Services, a 2.5 million-member state-mandated health-service. Patients with mNSCLC diagnosed between 2017 and 2018 were followed until December 2019. RESULTS: Among 434 patients (62% male, mean age 68 y, 74% adenocarcinoma), 345 (79%) initiated first-line treatment. Compared to treated, untreated patients (n = 89) were more likely to be older (mean [SD]=71 years [10] vs. 67 [10], p < 0.001), have a higher co-morbidity index (5.6 ([4.4] vs. 4.0 [3.4], p < 0.001), smokers (84% vs. 66%, p = 0.001), and require hospitalization in the year prior to diagnosis (80% vs 61%, p = 0.002). There was no difference in socioeconomic status. Time from first symptom to imaging was longer for untreated than treated patients (6.51 months [4.24, 7.33] vs 3.48 months [2.76, 4.34] respectively, p = 0.22). Predictors of treatment initiation included age< 70 years, non-smokers, EGFR testing performed, ECOG performance status 0-1 and shorter wait from first symptom to imaging. Median time from first symptom to initiation of 1 L, was 7.76 months (6.51-8.75). CONCLUSION: The proportion of untreated mNSCLC patients are comparable to those reported in the US; we did not find health disparities between socioeconomic levels. Our data suggest that the main barrier to effective diagnostic process is the wait between symptom complaint and imaging.

Real-world study of PD-L1 testing patterns and treatment distribution in patients with metastatic non-small-cell lung cancer in Israel.

Aim: We describe PD-L1 testing patterns and first-line treatment for patients with metastatic non-small-cell lung cancer in a 2.3 million-member state-mandated health service in Israel. Materials & methods: Newly diagnosed stage IV non-small-cell lung cancer patients initiating systemic anticancer treatment from 1 January 2017 until 31 December 2018 were identified from the national cancer registry and Maccabi Healthcare Service database and followed until 30 June 2019. Results: The cohort consisted of 410 patients; 58% males, median age 68 years, 70% current/former smokers, 81% adenocarcinoma, 14% had brain metastases, and Eastern Cooperative Oncology Group performance status was 46/17/37% for 0-1/2-4/unknown, respectively. A total of 80% tested for PD-L1 expression, of which 47% had tumor proportion score (TPS) ≥ 50%. A total of 95% with TPS ≥ 50% and no known tumor aberrations (including EGFR mutations, and translocations in ALK and ROS1) received first-line PD-1/PD-L1-inhibitor monotherapy, and 80% of untested/TPS < 50% received platinum doublets. Conclusion: Fast uptake of testing was observed, and treatment patterns showed high adherence to guidelines.

Lay abstract We describe PD-L1 testing patterns in a cohort of 410 patients with stage IV non-small-cell lung cancer. All patients were newly diagnosed and newly treated in the years 2017 and 2018. In this cohort, 58% were males, average age was 68 years and 70% were current or former smokers. In this, 80% were tested for PD-L1 expression and 95% of those with a tumor score of >50% and no other tumor receptor mutations received first-line PD-1/PD-L1-inhibitor monotherapy (most receiving pembrolizumab). Moreover, 80% of those untested for PD-L1 or with a low tumor proportion score (<50%) received chemotherapy. After introduction in 2017, a fast uptake of PD-L1 testing was observed, and treatment patterns showed high adherence to guidelines.

Synchronized release of Doxil and Nutlin-3 by remote degradation of polysaccharide matrices and its possible use in the local treatment of colorectal cancer.

A novel approach to the prevention of colorectal cancer (CRC) recurrence by the local, luminal application of the combined therapies: Nutlin-3 (NUT) and the liposomal preparation of doxorubicin, Doxil(*) (Doxil) is presented here. The two drug entities were loaded into calcium alginate beads, engineered to erode upon exposure to a de-crosslinking agent, to allow for the controlled, concomitant release of the two. The synchronized release-driven improved cytotoxicity of NUT and Doxil was tested in vitro in RKO (wild-type p53) and HT-29 (mutant p53) CRC cells, by measuring intracellular expression of p53, p21 and Mdm2, as well as monitoring cell proliferation and viable cell numbers. NUT treatment alone was identified to be cytotoxic exclusively towards RKO cells. However, coadministration of NUT enhanced Doxil's anti-proliferative effects and cell death induction in a synergistic manner in both cell types. It was also identified that combinatorial treatment in a wt p53 context affected the p53 pathway by elevating the expression of p53 and its target p21. The capability of the formulation to erode in the presence of a de-crosslinking agent was demonstrated in vivo in the cecum of the anesthetized rat using indomethacin as a poorly water-soluble PK probe.