Patterns of brain metastases response to immunotherapy with pembrolizumab.

PURPOSE: Central nervous system (CNS) metastases from lung cancers and melanoma, significantly contribute to morbidity and mortality. Despite advances in local therapies, there is a need for effective systemic treatments. Pembrolizumab, a PD-1 inhibitor, has shown promise for some patients with untreated brain metastases from melanoma and non-small cell lung cancer (NSCLC). This study aims to analyze the response of brain metastasis to pembrolizumab and associate characteristics like size and location with treatment outcome. METHODS: This retrospective study used imaging data from a phase II trial of pembrolizumab in melanoma or NSCLC patients with untreated brain metastases. MRI evaluations were conducted at 2 month intervals, with each brain metastasis treated as a distinct tumor for response assessment, based on modified RECIST criteria (maximum 5 lesions, 5 mm target lesions). RESULTS: Of 130 individual target metastases (> 5 mm), in 65 patients with NSCLC (90 metastases) and Melanoma (40 metastases), 32 (24.6%) demonstrated complete resolution, 24 (18.5%) had partial resolution, 32 (24.6%) were SD and 42 (32.3%) demonstrated PD. Those smaller than 10 mm were more likely to show complete resolution (p = 0.0218), while those ≥ 10 mm were more likely to have PR. There was no significant association between size, number or location (supratentorial vs. infratentorial) and lesion progression. The median time to metastatic lesion progression in the brain was 5.7-7 weeks. CONCLUSION: Pembrolizumab is effective in brain metastases from NSCLC and melanoma, showing response (CR + PR) in 43% and progression (PD) in 32% of metastases. With the median time to CNS progression of 5.7-7 weeks, careful radiographic monitoring is essential to guide timely local treatment decisions.

The Canadian Breast Cancer Symposium 2023 Meeting Report.

On 15-16 June 2023, healthcare professionals and breast cancer patients and advocates from across Canada met in Toronto, Ontario, for the 2023 Canadian Breast Cancer Symposium (CBSC.). The CBSC. is a national, multidisciplinary event that occurs every 2 years with the goal of developing a personalized approach to the management of breast cancer in Canada. Experts provided state-of-the-art information to help optimally manage breast cancer patients, including etiology, prevention, diagnosis, experimental biology, and therapy of breast cancer and premalignant breast disease. The symposium also had the objectives of increasing communication and collaboration among breast cancer healthcare providers nationwide and providing a comprehensive and real-life review of the many facets of breast cancer. The sessions covered the patient voice, the top breast cancer papers from different disciplines in 2022, artificial intelligence in breast cancer, systemic therapy updates, the management of central nervous system metastases, multidisciplinary management of ductal carcinoma in situ, special populations, optimization-based individual prognostic factors, toxicity management of novel therapeutics, survivorship, and updates in surgical oncology. The key takeaways of these sessions have been summarized in this conference report.

Latest clinical research in leptomeningeal disease (LMD)-a narrative review.

BACKGROUND AND OBJECTIVE: Leptomeningeal disease (LMD) is associated with poor survival and health-related quality of life (HRQoL). There is an urgent need for clinical research in this area to improve the outcomes. The purpose of this study is to summarize the areas of active clinical research in LMD, identify the knowledge gap, and suggest future research directions. METHODS: A narrative review of clinical trials in LMD was conducted based on a search in clinicatrials.gov using the search term "leptomeningeal" under "condition or disease". Clinical trials in patients with LMD arising from solid malignancy that were labelled as "not yet recruiting", "recruiting", "enrolling by invitation" or "active, not recruiting" were included. Studies which were deemed to have significant impact on future research direction in LMD were selected for discussion. KEY CONTENT AND FINDINGS: A total of 38 clinical trials were included. Of these 38 trials, 19 are discussed in this review, with focus on their research questions and impact on future research directions. Most of the studies that were not selected for discussion focused on biomarker-driven interventions. Four key areas of research were identified, namely the (I) diagnosis, response assessment or molecular profiling of LMD (n=2); (II) advances in radiotherapy (n=3); (III) intrathecal treatment (n=13); (IV) novel drug carrier for systemic treatment (n=1). The research questions in the 19 discussed clinical trials included the tumour microenvironment of LMD, the role of novel molecular techniques in LMD, combination of radiotherapy with drugs, and cell-based immunotherapy. Among these 19 studies, 11 were phase 1 trials, 3 were phase 2 or phase 1/2 trials, 2 were phase 3 or phase 2/3 trials and the study phase was not reported in the remaining 3 studies. The existing knowledge gaps are discussed, including the lack of primary site-specific prognostic tools, cost-effectiveness studies, dedicated HRQoL assessment tools for LMD and sequencing of treatment. CONCLUSIONS: The current clinical trials in LMD offer the promise to improve the diagnosis and treatment outcomes of patients with LMD. More research is needed to overcome the potential hurdles in the current treatment and bridge the knowledge gaps as identified in this review, to improve patients' quantity and quality of survival.

Advances in the Management of Central Nervous System Metastases in Non-Small Cell Lung Cancer.

Central nervous system (CNS) metastases are common among patients with non-small cell lung cancer (NSCLC). While the presence of brain metastases has historically portended poor prognosis, recent advances in local and systemic therapies have greatly improved outcomes for NSCLC patients with CNS involvement. Stereotactic radiology surgery (SRS) has emerged as an effective radiotherapy technique with fewer toxicities compared to whole brain radiotherapy (WBRT). Furthermore, multi-generation tyrosine kinase inhibitors (TKIs) with CNS overall response rates (ORR) of up to 70-80% are now an accepted first-line approach for a subset of advanced NSCLC patients with targetable molecular alterations. In addition, while the CNS was once considered an immunologic sanctuary site, growing evidence shows that immune checkpoint inhibitors (ICIs) can induce durable responses in brain metastases as well. Ongoing efforts to optimize CNS metastases management are necessary to refine multimodal treatment approaches and develop new therapeutics with better CNS penetrance.

A Phase II Single-arm Study of Palbociclib in Patients With HER2-positive Breast Cancer With Brain Metastases and Analysis of ctDNA in Patients With Active Brain Metastases.

INTRODUCTION: Palbociclib is highly efficacious and well tolerated in hormone-receptor positive (HR+) metastatic breast cancer (BC) but its activity for HER2+ BC with brain metastases (BM) is unknown. METHODS: In a single-arm phase II study we evaluated palbociclib with trastuzumab for patients with HER2+ MBC and BM. The primary endpoint was BM response rate. Circulating tumor DNA (ctDNA) was evaluated at baseline, and in a subset of patients at cycle 3 and progression. We also retrospectively identified additional patients with metastatic BC, active BM, and a ctDNA assessment prior to therapy for BM. RESULTS: Twelve patients with HER2+ MBC were enrolled, 4 with HR+ and 8 with HR- disease. No responses were seen. Best response was stable disease for 6 patients and progressive disease for 6 patients. The median PFS was 2.2 months, interquartile range (IQR) was 1.56 to 3.63 months. The median OS was 13.1 months and IQR was 9.4 to 23.8 months The CNS was the primary site of progression for all patients. The median variant allele fraction (VAF) of the dominant variant in each patient was 0.18% (interquartile range [IQR] 0.12%-0.47%) with a median number of somatic alterations of 1. We additionally evaluated ctDNA results from 26 patients with BC and active BM, among whom the median VAF was 11.8% (IQR 3.9%-27.3%) with a median number of alterations was 6 (IQR 4-9). Notably, progressive systemic disease was significantly less frequent in the trial cohort compared with additional retrospectively identified patients (8% vs. 81%). CONCLUSION: Palbociclib did not demonstrate activity in HER2+ MBC with BM. Patients with progressive BM but stable, responding, or absent systemic disease have low VAF and number of alterations detected by ctDNA analysis from blood.

A phase I/II study of intrathecal trastuzumab in human epidermal growth factor receptor 2-positive (HER2-positive) cancer with leptomeningeal metastases: Safety, efficacy, and cerebrospinal fluid pharmacokinetics.

BACKGROUND: Patients with human epidermal growth factor receptor 2-positive (HER2-positive) cancers have a high incidence of central nervous system (CNS) spread, but unfortunately systemic trastuzumab which targets the HER2 receptor has little CNS penetration. The purpose of this study was to determine the maximum-tolerated dose of intrathecal trastuzumab and its efficacy in patients with HER2-positive leptomeningeal disease (LMD). METHODS: This multicenter study enrolled 34 LMD patients in a combined phase I/II study in treating patients with intrathecal trastuzumab. Any HER2-positive histology was allowed in the phase I; the phase II was limited to HER2-positive breast cancer. RESULTS: Intrathecal trastuzumab was well-tolerated, with one dose limiting toxicity of grade 4 (arachnoiditis) occurring at the 80 mg twice weekly dose. The recommended phase II dose was 80 mg intrathecally twice weekly. Twenty-six patients at dose level 80 mg were included in evaluation for efficacy: partial response was seen in 5 (19.2%) patients, stable disease was observed in 13 (50.0%), and 8 (30.8%) of the patients had progressive disease. Median overall survival (OS) for phase II dose treated patients was 8.3 months (95% CI 5.2-19.6). The phase II HER2-positive breast cancer patients median OS was 10.5 months (95% CI 5.2-20.9). Pharmacokinetic (PK) studies were limited in the setting of concurrent systemic trastuzumab administration, however, did show stable cerebrospinal fluid (CSF) concentrations with repeated dosing suggest that trastuzumab does not accumulate in the CSF in toxic concentrations. CONCLUSION: This study suggests promise for potentially improved outcomes of HER-positive LMD patients when treated with intrathecal trastuzumab while remaining safe and well-tolerated for patients.

Activity of capecitabine for central nervous system metastases from breast cancer.

Purpose: Central nervous system (CNS) metastases are a significant burden in breast cancer (BC). Capecitabine is a frequent choice in this scenario, but data supporting its single-agent activity are scarce. We aimed to evaluate the intracranial efficacy of capecitabine in CNS metastases from BC. Methods: This retrospective cohort included patients with CNS metastases from BC treated with capecitabine at a single centre. Study endpoints were intracranial CNS objective response rate (CNS-ORR), intracranial CNS disease control rate (CNS-DCR), intracranial CNS progression-free survival (CNS-PFS) and overall survival (OS). Results: 209 patients were included; 41.6% hormone receptor-positive HER2-negative (HR + HER2-), 33.9% human epidermal growth factor receptor 2 positive (HER2+), and 26.4% triple-negative breast cancer (TNBC). Radiotherapy was performed in 90.4% and CNS surgery in 27.5%. Among patients accessible for intracranial response, 3-month CNS-ORR and CNS-DCR were 41.6% and 81.2%. CNS-ORR was numerically higher among TNBC (61% versus 38% in HR + HER2-BC and 35% in HER2 + BC) (p = 0.194). When considering patients who were not evaluable at 3-month as non-responders, the 3-month CNS-ORR was 19.1% (18.4% in HR + HER2-, 18.3% in HER2+, and 21.6% in TNBC). Nevertheless, TNBC was associated with lower CNS-PFS (p < 0.001) and OS (p < 0.001). Median PFS was 8.3 months in HR + HER2-, 5.0 months in HER2+, and 3.0 months in TNBC. Median OS was 8.7, 9.1 and 4.5 months, respectively. Conclusion: Among patients with BC and CNS metastases accessible for intracranial response at 3 months, intracranial activity was observed with capecitabine. These patients have a poor prognosis regardless of the BC subtype, especially in scenarios where newer therapeutic options are unavailable.

Phase 1 study of intraventricular 131I-omburtamab targeting B7H3 (CD276)-expressing CNS malignancies.

BACKGROUND: The prognosis for metastatic and recurrent tumors of the central nervous system (CNS) remains dismal, and the need for newer therapeutic targets and modalities is critical. The cell surface glycoprotein B7H3 is expressed on a range of solid tumors with a restricted expression on normal tissues. We hypothesized that compartmental radioimmunotherapy (cRIT) with the anti-B7H3 murine monoclonal antibody omburtamab injected intraventricularly could safely target CNS malignancies. PATIENTS AND METHODS: We conducted a phase I trial of intraventricular 131I-omburtamab using a standard 3 + 3 design. Eligibility criteria included adequate cerebrospinal fluid (CSF) flow, no major organ toxicity, and for patients > dose level 6, availability of autologous stem cells. Patients initially received 74 MBq radioiodinated omburtamab to evaluate dosimetry and biodistribution followed by therapeutic 131I-omburtamab dose-escalated from 370 to 2960 MBq. Patients were monitored clinically and biochemically for toxicity graded using CTCAEv 3.0. Dosimetry was evaluated using serial CSF and blood sampling, and serial PET or gamma-camera scans. Patients could receive a second cycle in the absence of grade 3/4 non-hematologic toxicity or progressive disease. RESULTS: Thirty-eight patients received 100 radioiodinated omburtamab injections. Diagnoses included metastatic neuroblastoma (n = 16) and other B7H3-expressing solid tumors (n = 22). Thirty-five patients received at least 1 cycle of treatment with both dosimetry and therapy doses. Acute toxicities included < grade 4 self-limited headache, vomiting or fever, and biochemical abnormalities. Grade 3/4 thrombocytopenia was the most common hematologic toxicity. Recommended phase 2 dose was 1850 MBq/injection. The median radiation dose to the CSF and blood by sampling was 1.01 and 0.04 mGy/MBq, respectively, showing a consistently high therapeutic advantage for CSF. Major organ exposure was well below maximum tolerated levels. In patients developing antidrug antibodies, blood clearance, and therefore therapeutic index, was significantly increased. In patients receiving cRIT for neuroblastoma, survival was markedly increased (median PFS 7.5 years) compared to historical data. CONCLUSIONS: cRIT with 131I-omburtamab is safe, has favorable dosimetry and may have a therapeutic benefit as adjuvant therapy for B7-H3-expressing leptomeningeal metastases. TRIAL REGISTRATION: clinicaltrials.gov NCT00089245, August 5, 2004.

Progressive vision loss as the initial symptom of Prostate Cancer.

Althought it may vary between countries, since the prostate specific antigen screening era, metastasic prostate cancer at diagnosis accounts for approximately 10% of cases. Intracranial dural metastases are uncommon, but when present they may lead to an increase in intracranial pressure that can subsequently damage intracranial structures, such as the cranial nerves. Prolonged intracranial hypertension can cause optic nerve ischemia, leading to progressive and irreversible vision loss if untreated, hence the importance of anamnesis, complete physical examination, and clinical suspicion.

Novel approaches to the management of patients with 5-15 brain metastases: a narrative review.

BACKGROUND AND OBJECTIVE: The management of metastatic disease has been greatly influenced by molecular-based tumor classification and associated therapeutic targets, leading to a significant improvement in survival in many cases. This improvement, in both progression free survival and overall survival, has led to an increased incidence of brain metastases (BM) in a population with systemically well controlled disease or patients with promising therapeutic options available. Within this review, we discuss the paradigm of treatment for 5 to 15 BM, and how the treatment has evolved away from short-term palliation towards providing long term intracranial control. METHODS: A review of literature pertaining to treatment of multiple BM was performed. We searched in PubMed to identify literature on treatment of multiple brain metastases. Only English literature published until February 1st, 2022 was reviewed. KEY CONTENT AND FINDINGS: The management of 5-15 BM include multi-modality treatment pathways that are tailored towards each individual's primary cancer and burden of disease. Surgical resection of a dominant metastasis is still reserved for large symptomatic lesions, and is combined with post-operative local disease control. Overall, there is a shift away from whole brain radiation therapy (WBRT) due to side effect profile towards stereotactic radiosurgery (SRS). However, advances in WBRT continue to be studied, as well as the use of immunotherapy, targetable mutations, and synergistic effects between SRS and targeted therapies. CONCLUSIONS: The use of SRS to treat 5 to 15 BM is an increasingly acceptable and well-regarded practice, along with a combinatorial approach taking into account systemic options during all treatment timepoints.

Clinicopathological characteristics and prognosis of breast cancer patients with isolated central nervous system metastases in the multicentre ESME database.

BACKGROUND: As a result of progress in diagnosis and treatment, there is a growing prevalence of metastatic breast cancer (MBC) with isolated CNS metastases. This study describes the largest-to-date real-life cohort of this clinical setting and compares it to other clinical presentations. METHODS: We retrospectively analysed the French Epidemiological Strategy and Medical Economics (ESME) MBC database including patients who initiated treatment for MBC between 2008 and 2016. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Descriptive statistics and multivariate Cox model were used. RESULTS: Of 22,266 patients, 647 (2.9%) and 929 (4.2%) patients had isolated first-site CNS metastases or combined with extra-CNS metastases, with longer OS for the group with isolated CNS metastases (16.9 versus 13.9 months, adjusted HR = 1.69 (95% CI: 1.50-1.91), p < 0.001). Among the 541 (2.4%) patients with isolated CNS metastases and no intrathecal therapy (excluding leptomeningeal metastases), HER2+ cases were preponderant over TN or HR+ /HER2- cases (41.6% versus 26.1% versus 28.5%, respectively, p < 0.01). The treatment strategy consisted of a combination of local treatment and systemic therapy (49.2%), local treatment only (35.5%) or systemic therapy only (11.4%), or symptomatic therapy only (3.9%). Median PFS was 6.1 months (95% CI: 5.7-6.8). Median OS was 20.7 months (95% CI: 17.3-24.3), reaching 37.9 months (95% CI: 25.9-47.6) in the HR+ /HER2+ subgroup. Older age, TN subtype, MBC-free interval of 6-12 months, lower performance status, and WBRT were associated with poorer survival. Patients who received systemic therapy within 3 months from MBC diagnosis had longer OS (24.1 versus 16.1 months, p = 0.031), but this was not significant on multivariate analysis [HR = 1.0 (95% CI: 0.7-1.3), p = 0.806]. CONCLUSIONS: Patients with isolated CNS metastases at MBC diagnosis represent a distinct population for which the role of systemic therapy needs to be further investigated in prospective studies.

Treatment patterns and clinical outcomes for patients with melanoma and central nervous system metastases: A real-world study.

BACKGROUND: Patients with melanoma and central nervous system (CNS) metastases have poor survival outcomes. We investigated real-world treatment patterns and overall survival (OS) of patients with melanoma and CNS metastases. METHODS: A retrospective analysis utilizing a nationwide de-identified electronic health record-derived database was undertaken in patients diagnosed with advanced melanoma between January 2011 and September 2018. Patients with any visit ≤90 days of metastatic diagnosis and with confirmed CNS metastases were included. RESULTS: Of 3473 patients diagnosed with advanced melanoma, 791 patients with confirmed CNS metastases were identified and included in this analysis. Synchronous CNS metastasis (≤30 days of metastatic diagnosis) was associated with longer median OS than metachronous CNS metastasis (>30 days after metastatic diagnosis, 0.58 vs 0.42 years). Stereotactic radiosurgery (SRS) was the most common treatment (40.5%) alone or in combination with other local or systemic therapies, being more frequent in patients diagnosed in 2015+ versus 2011-2014 (44.1% vs 35.5%, respectively). The most common systemic treatment was immune checkpoint inhibitors (ICIs; 30.5%), predominantly anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) alone (2011-2014) and anti-programmed death-1 alone or in combination with anti-CTLA-4 (2015+). Median OS was longest in SRS-treated patients (1.17 years) regardless of number of CNS metastases. Median OS for SRS-treated patients increased from 0.83 years (2011-2014) to 1.75 years (2015+). In multivariable analysis, the effect of SRS remained significant after adjustment for sex, race, intracranial and extracranial disease burden, and timing of CNS metastases. Interaction testing to examine potential synergy between SRS/whole-brain radiation therapy and ICIs found no significant interaction. CONCLUSIONS: Despite advances in treatment, patients with melanoma and CNS metastases have poor survival outcomes. Prevalence of SRS increased over time and was associated with improved outcomes.

Ensartinib in advanced ALK-positive non-small cell lung cancer: a multicenter, open-label, two-staged, phase 1 trial.

Background: Ensartinib, a potent second-generation tyrosine kinase inhibitor (TKI) that targets anaplastic lymphoma kinase (ALK), MET and ROS1, was evaluated in a phase I clinical trial in patients with advanced, ALK-rearranged non-small cell lung cancer (NSCLC). Methods: Patients with advanced, ALK or ROS1-positive NSCLC were recruited from 2 centers in China. This study consisted of dose escalation and expansion stages. Patients were treated with oral ensartinib [dosage of escalation stage was from 150, 200, 225 to 250 mg per day, expansion stage was recommended phase II dose (RP2D)] in continuous 28-day cycles. The primary objectives were safety, dose limited toxicity (DLT), maximum tolerated dose (MTD), and RP2D based on tolerability. Key secondary objectives included pharmacokinetic (PK) and anti-tumor activity. Results: Forty-eight patients were enrolled, 37 (77.1%) were ALK TKI-naïve, 11 (22.9%) patients had previously received crizotinib, ceritinib or alectinib. Ensartinib was well tolerated and common treatment-related adverse events (TRAEs) included rash (87.5%), transaminase elevation (60.4%), pruritus (45.8%) and creatinine elevation (35.4%). The top 3 grade 3-5 TRAEs were rash (14.6%), elevated alanine aminotransferase (ALT) (12.5%) and aspartate transaminase (AST) (4.2%). Two DLTs were observed in 250 mg, so MTD and RP2D was 225 mg per day. Ensartinib was moderately absorbed (median Tmax: 3.00-4.00 h) and slowly eliminated (mean T1/2: 21.0-30.2 h). The area under the curve (AUC) of ensartinib reached saturation at 200 to 225 mg and no major accumulation after daily administration. For all patients, the objective response rate (ORR) and disease control rates (DCR) were 64.6 % and 81.3%, median progression-free survival (mPFS) was 16.79 months. In subgroup analysis, the ORR and mPFS was 81.3% and 45.5%, 25.73 and 4.14 months in TKI-naïve and -treated ALK+ patients, respectively. The intra-cranial ORR and mPFS for patients with measurable brain metastases were 66.7% and 22.90 months. ALK abundance may predict the efficacy of ensartinib. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed specific signaling pathways enrichment in long and short progression-free survival (PFS) groups. Conclusions: Ensartinib was well tolerated under 225 mg (MTD) and demonstrated promising anti-tumor activity in ALK+ NSCLC patients, including those with CNS metastases and those previously TKI-treated. Trial Registration: ClinicalTrials.gov NCT02959619.

Emergent immunotherapy approaches for brain metastases.

Brain metastases from solid tumors are increasing in incidence, especially as outcomes of systemic therapies continue to extend patients' overall survival. The long-held notion that the brain is an immune sanctuary has now been largely refuted with increasing evidence that immunotherapy can induce durable responses in brain metastases. Single agent immune checkpoint inhibition with anti-CTLA4 and anti-PD1 antibodies induces durable responses in 15%-20% in melanoma brain metastases as long as patients are asymptomatic and do not require corticosteroids. The combination of anti-CTLA4 with anti-PD-1 antibodies induces an intracranial response in over 50% of asymptomatic melanoma patients, and much lower rate of otherwise durable responses (20%) in symptomatic patients or those on steroids. Data in other cancers, such as renal cell carcinoma, are accumulating indicating a role for immunotherapy. Emerging immunotherapy approaches will have to focus on increasing response rates, decreasing toxicity, and decreasing steroid dependency. The path to those advances will have to include a better understanding of the mechanisms of response and resistance to immunotherapy in brain metastases, the use of novel agents such as anti-LAG3 checkpoint inhibitors, targeted therapy (oncogene directed or TKIs), and possibly surgery and SRS to improve the outcomes of patients with brain metastases.

A plain language summary of results from the ADAURA study: osimertinib after surgery for patients who have early-stage EGFR-mutated non-small cell lung cancer.

Here, we summarize the initial results from the ADAURA clinical study looking at treatment with osimertinib in patients with a specific type of non-small cell lung cancer (also called NSCLC). Osimertinib (TAGRISSO®) is a medication used to treat a type of NSCLC with a change (mutation) in the EGFR gene, known as EGFR-mutated NSCLC. EGFR stands for 'epidermal growth factor receptor'. It is a protein present on the surface of both healthy and cancer cells that can regulate how cells grow and divide. Sometimes, certain mutations in EGFR can result in the EGFR protein malfunctioning, which can lead to the formation of cancer, like EGFR-mutated NSCLC. Based on previous clinical studies, osimertinib is already approved for use in patients with EGFR-mutated NSCLC that has spread beyond the lung (metastatic disease). This medication works to stop, prevent, or slow the growth of EGFR-mutated NSCLC tumors, by specifically blocking the activity of EGFR. In the ADAURA clinical study, participants had resectable EGFR-mutated NSCLC, which means they had tumors that can be removed by surgery. Participants took either osimertinib or a placebo (a dummy drug with no active ingredient) after having their tumors removed by surgery. Post-surgery chemotherapy was allowed, but not compulsory (this was decided by the participant and their doctor). To date, the study has shown that osimertinib could be beneficial for patients with resectable EGFR-mutated NSCLC. Participants who took osimertinib have stayed cancer-free for longer than those who took the placebo, regardless of whether or not they received chemotherapy after surgery. Osimertinib treatment also reduced the risk of tumors spreading to the brain and spinal cord, otherwise known as the central nervous system (also called CNS). The side effects experienced by the participants taking osimertinib have been consistent with what we already know. Based on the results from ADAURA, osimertinib has been approved for the treatment of resectable EGFR-mutated NSCLC after tumor removal. The ADAURA study is still ongoing and more results are expected to be released in the future. ClinicalTrials.gov NCT number: NCT02511106.

Analysis of the pan-Asian subgroup of patients in the NALA Trial: a randomized phase III NALA Trial comparing neratinib+capecitabine (N+C) vs lapatinib+capecitabine (L+C) in patients with HER2+metastatic breast cancer (mBC) previously treated with two or more HER2-directed regimens.

PURPOSE: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥ 2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein. METHODS: 621 centrally assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid, day 1-14) with loperamide prophylaxis or to L (1250 mg qd) + C (1000 mg/m2 bid, day 1-14) in 21-day cycles. Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety. RESULTS: 104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P = 0.039). Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P < 0.0001) were extended with N+C, compared to L+C. The incidences of grade 3/4 treatment emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were mostly comparable between the two arms. Diarrhea and palmar-plantar erythrodysesthesia were the most frequent TEAEs in both arms, similar to the overall population in incidence and severity. CONCLUSION: Consistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥ 2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted. CLINICAL TRIAL REGISTRATION: NCT01808573.

How we treat HER2-positive brain metastases.

Overexpression of the human epidermal growth factor 2 (HER2)/neu glycoprotein receptor in breast cancer is associated with increased risk of brain metastases, especially in patients with advanced disease. Improvements in the treatment of HER2-positive breast cancer has led to prolonged survival of patients with advanced disease, but the prevention and management of central nervous system metastases still poses unique clinical challenges given the associated morbidity and mortality of this site of disease. HER2-positive brain metastases are treated with surgery, radiation (stereotactic radiosurgery or whole brain radiotherapy), and systemic therapies, and are best managed by an experienced multidisciplinary team. The present article aims to provide an overview to our approach to treatment of HER2-positive brain metastases, including a review of agents with central nervous system activity, as well as management suggestions for several nuanced clinical scenarios.

Efficacy of lorlatinib treatment in ALK rearrangement lung cancer with severe symptomatic central nervous system metastases and poor performance status.

Lorlatinib treatment should be positively considered even for patients with ALK-positive NSCLC with severe neurocognitive disturbance and poor performance status due to CNS metastases, including leptomeningeal carcinomatosis.