Efficacy and tolerability of capmatinib in a very elderly patient with metastatic NSCLC harboring a MET exon 14 mutation.

We report the case of an 87-year-old female patient who was diagnosed with metastatic non-small-cell lung cancer harboring MET exon 14 skipping mutation (MET ex14) and PD-L1 expression of 60%. A first-line treatment with atezolizumab was started with primary resistance. Then, a second-line treatment with capmatinib, a selective type Ib MET tyrosine kinase inhibitor, was started, achieving a partial response. The patient is still alive and on treatment with capmatinib 300 mg twice daily after 20 months, with a good tolerability and no evidence of disease progression.In summary, our patient experienced a long-lasting response (>18 months) with capmatinib as second-line treatment. Further analyses evaluating the efficacy and tolerability of MET tyrosine kinase inhibitors are warranted, especially in the elderly, a non-small-cell lung cancer population whose tumors could more frequently harbor MET ex14 mutation.

[Box: see text].

Integrated PBPK-EO modeling of osimertinib to predict plasma concentrations and intracranial EGFR engagement in patients with brain metastases.

The purpose of this study was to develop and validate a physiologically based pharmacokinetic (PBPK) model combined with an EGFR occupancy (EO) model for osimertinib (OSI) to predict plasma trough concentration (Ctrough) and the intracranial time-course of EGFR (T790M and L858R mutants) engagement in patient populations. The PBPK model was also used to investigate the key factors affecting OSI pharmacokinetics (PK) and intracranial EGFR engagement, analyze resistance to the target mutation C797S, and determine optimal dosing regimens when used alone and in drug-drug interactions (DDIs). A population PBPK-EO model of OSI was developed using physicochemical, biochemical, binding kinetic, and physiological properties, and then validated using nine clinical PK studies, observed EO study, and two clinical DDI studies. The PBPK-EO model demonstrated good consistency with observed data, with most prediction-to-observation ratios falling within the range of 0.7 to 1.3 for plasma AUC, Cmax, Ctrough and intracranial free concentration. The simulated time-course of C797S occupancy by the PBPK model was much lower than T790M and L858R occupancy, providing an explanation for OSI on-target resistance to the C797S mutation. The PBPK model identified ABCB1 CLint,u, albumin level, and EGFR expression as key factors affecting plasma Ctrough and intracranial EO for OSI. Additionally, PBPK-EO simulations indicated that the optimal dosing regimen for OSI in patients with brain metastases is either 80 mg once daily (OD) or 160 mg OD, or 40 mg or 80 mg twice daily (BID). When used concomitantly with CYP enzyme perpetrators, the PBPK-EO model suggested appropriate dosing regimens of 80 mg OD with fluvoxamine (FLUV) itraconazole (ITR) or fluvoxamine (FLUC) for co-administration and an increase to 160 mg OD with rifampicin (RIF) or efavirenz (EFA). In conclusion, the PBPK-EO model has been shown to be capable of simulating the pharmacokinetic concentration-time profiles and the time-course of EGFR engagement for OSI, as well as determining the optimum dosing in various clinical situations.

Erythema dyschromicum perstans-like eruptions induced by epidermal growth factor receptor inhibitors in patients with lung cancer.

INTRODUCTION: Cutaneous adverse reactions to epidermal growth factor receptor inhibitors (EGFRi) are some of the most common side effects that patients experience. However, cutaneous adverse reactions that cause dyspigmentation in patients have been rarely reported. Erythema dyschromicum perstans (EDP) is a rare pigmentary condition that causes ashy-grey hyperpigmented macules and patches, with a few cases reported from EGFRi in the literature. The disfiguration caused by this condition may negatively impact patients' quality of life. Our study aimed to describe the clinical characteristics of EDP induced by EGFRi to better recognize and manage the condition. METHODS: We conducted a multicenter retrospective review at three academic institutions to identify patients with EDP induced by EGFRi from 2017 to 2023 and included sixteen patients in our study. RESULTS: The median age of patients was 66 years old, with 63% female and 37% male (Table 1). The majority of our patients were Asian (88%). All patients had non-small cell lung cancer and most patients received osimertinib. Median time to EDP was 6 months. The most common areas of distribution were the head/neck region, lower extremities, and upper extremities. Various topical ointments were trialed; however, approximately less than half had improvement in their disease and most patients had persistent EDP with no resolution. All patients desired treatment except one with EDP on the tongue, and there was no cancer treatment discontinuation or interruption due to EDP. Table 1 Patient demographics and clinical characteristics of 16 patients with EDP induced by EGFRi Case no Demographics: age, race, and sex Fitzpatrick skin type Cancer type EGFR therapy Concomitant photosensitive drug(s) Time to EDP (months) Clinical features Distribution Symptoms Treatments and clinical course EDP status from most recent follow up 1 47 y/o Asian male III Stage IV NSCLC Erlotinib None Unknown Brown-blue-gray hyperpigmented patches Bilateral shins Left thigh Xerosis Pruritus Triamcinolone 0.1% ointment for 4 months, improvement of blue discoloration Tacrolimus 0.1% BID for 9 months, improvement but no resolution Ongoing 2 62 y/o Asian female IV Stage IV NSCLC Osimertinib None 4 Gray-brown hyperpigmented patches Bilateral arms Back Forehead Neck Right shin None Tacrolimus 0.1% ointment for 1 year with minor improvement Ongoing 3 69 y/o Asian female IV Stage IV NSCLC Osimertinib None 4 Gray-brown macules and patches Chest Face Forehead Bilateral legs None Tacrolimus 0.1% ointment for 10 months, no improvement Ongoing 4 79 y/o White male II Stage IV NSCLC Osimertinib None 15 Mottled grey-blue hyperpigmented patches and plaques with mild scaling Bilateral arms Back Forehead Neck None Photoprotection, no improvement Ongoing 5 69 y/o Asian female III Stage IV NSCLC Osimertinib Ibuprofen 4 Blue-grey hyperpigmented macules and patches Abdomen Bilateral arms None Tacrolimus 0.1% ointment for 7 months, no improvement Ongoing 6 65 y/o Asian male III Stage IV NSCLC Osimertinib None 20 Hyperpigmented blue gray macules and patches Helix Bilateral shins None Photoprotection, no improvement Ongoing 7 66 y/o Asian female IV Stage IV NSCLC Erlotinib TMP-SMX 6 Ashy grey-brown thin plaques Back Forehead None 2.5% hydrocortisone ointment for 8 months, resolved Resolved 8 82 y/o Asian male III Stage III NSCLC Erlotinib Simvastatin 20 Ash-grey hyperpigmented patches Dorsal feet Forehead Scalp None Photoprotection Ongoing 9 57 y/o Asian female III Stage II NSCLC Erlotinib None 1 Bue-grey discoloration Tongue None No intervention Ongoing 10 51 y/o Asian female III Stage IV NSCLC Osimertinib None 9 Blue-grey hyperpigmented macules and patches Bilateral arms Axillae Groin Neck Trunk None 2.5% hydrocortisone ointment, triamcinolone 0.1% ointment, photoprotection with mild improvement Ongoing 11 67 y/o Asian male III Stage IV NSCLC Osimertinib None 7 Gray-blue macules and patches with mild background erythema and scaling Bilateral arms Ears Face Bilateral shins None Triamcinolone 0.1% ointment, protection for 6 months with mild improvement Ongoing 12 75 y/o Asian female IV Stage III NSCLC Osimertinib TMP-SMX 3 Gray-blue hyperpigmented patches Bilateral arms Abdomen Back Face Bilateral shins Pruritus Triamcinolone 0.1% and betamethasone 0.01% with relief of pruritus, lesions unchanged Triluma cream 6 months, mild improvement Ongoing 13 42 y/o Asian male IV Stage IV NSCLC Afatinib TMP-SMX 24 Grey-brown hyperpigmented patches Back Face None Hydroquinone 4% cream for 2 years with mild improvement Ongoing 14 74 y/o White female III Stage II NSCLC Osimertinib Atorvastatin 4 Grey-brown hyperpigmented patches Bilateral legs Trunk None Photoprotection Ongoing 15 64 y/o Asian female IV Stage IV NSCLC Osimertinib None 3 Gray-brown hyperpigmentation Abdomen Bilateral arms Back Bilateral legs Pruritus Triamcinolone 0.1% cream; No change, minimal concern to patient Ongoing 16 52 y/o Asian female IV Stage IV NSCLC Osimertinib None 42 Gray hyperpigmented patches with digitate shape Abdomen Bilateral flanks None Triamcinolone 0.1% cream Ongoing NSCLC, non-small cell lung cancer, TMP-SMX, Trimethoprim/Sulfamethoxazole CONCLUSIONS: We highlight the largest case series describing EDP from EGFR inhibitors, which mostly affected Asian patients with lung malignancy and on EGFR tyrosine kinase inhibitors. Clinicians should be able to recognize this condition in their patients and assess how it is affecting their quality of life, and refer to dermatology to help with management.

Capmatinib plus nivolumab in pretreated patients with EGFR wild-type advanced non-small cell lung cancer.

INTRODUCTION: Dysregulated MET is an established oncogenic driver in non-small cell lung cancer (NSCLC). MET signaling may also suppress anticancer immune responses. Concomitant MET inhibition with capmatinib (a MET inhibitor) synergistically enhanced the efficacy of immunotherapies in murine cancer models, regardless of tumor dependency to MET signaling. Here, we report results of a multicenter, open-label, phase 2 study of capmatinib plus nivolumab (a PD-1 inhibitor) in patients with EGFR wild-type advanced NSCLC, previously treated with platinum-based chemotherapy. METHODS: Patients were allocated into high-MET or low-MET groups according to MET expression determined by immunohistochemistry, MET gene copy number as assessed by fluorescence in-situ hybridization, and presence of MET exon 14 skipping mutation, then received capmatinib 400 mg, oral, twice daily in combination with nivolumab 3 mg/kg intravenously every 2 weeks. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate per RECIST v1.1. RESULTS: The primary endpoint was met in both the high-MET (N = 16) and low-MET (N = 30) groups. In the high-MET and low-MET groups, respectively, the estimated mean 6-month PFS rate (95 % credible interval) by Bayesian analysis was 68.9 % (48.5-85.7) and 50.9 % (35.6-66.4). The Kaplan-Meier median PFS (95 % CI) was 6.2 months (3.5-19.2) and 4.2 months (1.8-7.4). The overall response rate (95 % CI) was 25.0 % (7.3-52.4) and 16.7 % (5.6-34.7). Most frequent treatment-related adverse events (≥30 % any grade, N = 46) were nausea (52.2 %), peripheral edema (34.8 %), and increased blood creatinine (30.4 %). CONCLUSIONS: Capmatinib plus nivolumab showed clinical activity and manageable safety in pretreated patients with advanced EGFR wild-type NSCLC, independent of MET status. TRIAL REGISTRATION: ClinicalTrials.gov NCT02323126.

Efficacy of first-line dual oral pyrotinib plus capetabine therapy in HER2-positive metastatic breast cancer: A real-world retrospective study.

BACKGROUND: The combination of dual-targeted human epidermal growth factor receptor 2 (HER2) therapy and chemotherapy is the standard first-line regimen for recurrent/metastatic breast cancer (mBC). However, the toxicity of such combination therapy can lead to some patients being unable to tolerate adverse events or bear treatment costs. As a novel irreversible pan-ErbB receptor TKI (pyrotinib), can the dual oral administration of pyrotinib plus capetabine (PyroC) provide first-line survival benefits and serve as a more affordable treatment option? METHODS: This real-world retrospective study included patients diagnosed with HER2-positive mBC who received PyroC as a first-line treatment at West China Hospital between May 2018 and July 2023. The survival data and toxicity profiles were reported in this study. RESULTS: A total of 64 patients received PyroC as first-line therapy. The median progression-free survival (PFS) was 19.6 months (95% CI 15.0-27.2), while overall survival (OS) has not yet been reached. Kaplan-Meier analysis indicated that age (≥60, p = 0.03) and metastasis sites (p = 0.004) were related to poor efficacy of PyroC, while there was no relationship between effectiveness and menstrual status, hormone receptor (HR) status or previous treatment with anti-HER2 therapy. Furthermore, the objective response rate (ORR) and disease control rate (DCR) were 79.7% and 98.4%, respectively. Of the patients, 78.1% reported treatment-related adverse events (TRAEs). The predominant adverse events were diarrhea (n = 46, 71.9%) and hand-foot syndrome (n = 10, 15.6%). CONCLUSION: The dual oral administration regimen (PyroC) has a promising ORR or PFS in HER2-positive mBC patients, with an acceptable safety profile and convenience.

Effectiveness and Safety of Pyrotinib-Based Therapy in the Treatment of HER2-Positive Breast Cancer Patients with Brain Metastases: A Multicenter Real-World Study.

BACKGROUND: Approximately 30% to 50% of patients with human epidermal growth factor receptor 2-positive metastatic breast cancer develop brain metastasis (BMs). Pyrotinib has shown promising efficacy in these patients. However, real-world evidence supporting its use is scarce. Therefore, we evaluate the efficacy and safety of pyrotinib-based regimens in the real world. MATERIALS AND METHODS: We enrolled patients with BMs from various healthcare facilities in China's Shandong region and used an updated breast-graded prognostic assessment (breast-GPA) to predict survival outcomes. RESULTS: Efficacy and toxicity were assessed in 101 patients. Overall, the median progression-free survival (PFS) was 11.0 months (95% CI, 7.6-14.4 months). PFS was shorter in patients with a breast-GPA of 0 to 2.0 (P< .001). Previous treatment with pertuzumab plus trastuzumab (P = .039) and varying numbers of BMs (P = .028) had a significant positive correlation with PFS. Additionally, radiotherapy (P = .033) for BMs, especially pyrotinib concurrent with radiotherapy (P = .013), significantly prolonged the PFS. In patients with a breast-GPA of 0 to 2.0, a significant difference in PFS was observed depending on whether the brain was the first metastatic site (P< .001). Furthermore, a breast-GPA (0-2.0 vs. 2.5-4.0), and radiotherapy for BMs were found to be independent predictors of PFS. Overall, the objective response rate was 42.6%, while the disease control rate was 88.1%. Diarrhea emerged as the most common adverse event. CONCLUSION: Pyrotinib-based therapy is effective and tolerable in human epidermal growth factor receptor 2-positive metastatic breast cancer with BMs. Patients who underwent radiotherapy for BMs, particularly those who received pyrotinib concurrently with radiotherapy, exhibited a more favorable prognosis.

Multi-institutional study of osimertinib dose-optimization in non-small cell lung cancer patients with EGFR activating mutation aged 70 years or older ('MONEY' trial).

Osimertinib is the standard of care for patients with epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer. Dose-toxicity has been previously reported, but no dose-response data within the range of 20-240 mg daily (mg/d). Thus, the current 80 mg/d dosing might be too high for elderly Japanese patients with an average body weight of only 50 kg, resulting in excessive toxicity and cost. We therefore initiated a study to investigate whether osimertinib at 40 mg/d is non-inferior to 80 mg/d in patients with advanced or recurrent epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer aged ≥70 years, using a regression discontinuity design. Osimertinib is administered at 40 mg/d for body weight ≤50 kg, and 80 mg/d for body weight >50 kg. The primary endpoint is progression-free survival. Sample size is 550 patients, based on a non-inferiority margin of the progression-free survival hazard ratio 1.333, 0.10 one-sided type I error and 80% power.

Effect of early dose reduction of osimertinib on efficacy in the first-line treatment for EGFR-mutated non-small cell lung cancer.

Osimertinib is used as the first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, early dose reduction is often required due to adverse events (AEs). This study aimed to evaluate the effect of early dose reduction of osimertinib on efficacy and safety. This was a retrospective study including patients with EGFR-mutated NSCLC who were started on osimertinib as the first-line therapy between August 2018 and December 2021. Patients whose doses were reduced to less than 80 mg/day within 6 months of osimertinib initiation or started at 40 mg/day were defined as the dose reduction group. The primary endpoint was progression-free survival (PFS). Factors affecting PFS were explored using the Cox proportional hazards model. A total of 85 patients were included in this study. No significant differences in patient characteristics were observed between the dose reduction (n = 25) and standard dose groups (n = 60). The median PFS in the dose reduction group was significantly prolonged compared with that in the standard dose group (26.0 months vs. 12.0 months, p = 0.03). Multivariable analysis of 84 patients, excluding a patient with unknown brain metastasis, revealed that EGFR exon 21 L858R mutation, malignant pleural effusion or pleural metastasis, liver metastasis, and dose reduction within 6 months were independent factors affecting PFS. Early dose reduction of osimertinib is an effective therapeutic strategy for prolonging PFS in patients with EGFR-mutated NSCLC.

Furmonertinib and intrathecal pemetrexed chemotherapy rechallenges osimertinib-refractory leptomeningeal metastasis in a non-small cell lung cancer patient harboring EGFR20 R776S, C797S, and EGFR21 L858R compound EGFR mutations: a case report.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered the first-line treatment for advanced or metastatic non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, due to the rarity of cases, the response of EGFR-TKIs in patients harboring uncommon compound EGFR mutations still needs to be determined. Here, we demonstrated the case of a 47-year-old smoker diagnosed with leptomeningeal metastasis from NSCLC and had EGFR20 R776S, C797S, and EGFR21 L858R compound mutations. He was treated with furmonertinib combined with intrathecal pemetrexed chemotherapy following progression on osimertinib, which led to clinical improvement and successfully prolonged his survival by 3 months. Regrettably, the patient eventually died from heart disease. This report provides the first reported evidence for the use of furmonertinib and intrathecal pemetrexed chemotherapy in NSCLC patients harboring EGFR R776S/C797S/L858R mutations who progressed on previous EGFR-TKIs.

Early dose reduction of osimertinib in advanced EGFR -mutated non-small cell lung cancer.

Osimertinib has become the standard of care for epidermal growth factor receptor ( EGFR )-mutated non-small cell lung cancer (NSCLC). In order to prevent or treat toxicity, the osimertinib dose may be reduced. However, data regarding the impact of dose reduction during treatment are limited. We aimed to compare the efficacy of osimertinib early dose reduction during the first 3 months of treatment with late dose reduction in EGFR -mutated advanced NSCLC. This retrospective study included patients with EGFR -mutated advanced NSCLC who received osimertinib. We constituted two groups: 'early dose reduction' (early) with patients receiving a reduced dose of osimertinib from 80 to 40 mg within the 3 months of osimertinib initiation and 'late dose reduction' (late) with patients receiving a reduced dose after 3 months of full-dose treatment. Thirty-five patients were included, with 17 and 18 patients in the early and late groups, respectively, and a higher median age in the early group (76 vs. 67 years). The real-world progression-free survival (rwPFS) at 1 year was 70.5% in the early group and 88.9% in the late group ( P  = 0.31). Median rwPFS was 32.7 and 24.6 months ( P  = 0.98), and the median overall survival was 46.9 versus not reached in early and late groups, respectively ( P  = 0.17). Central nervous system rwPFS was not different between the early and late groups: 29.8 and 35.8 months, respectively ( P  = 0.39). We showed that a reduced dose of osimertinib within the first 3 months of treatment, compared to a later reduced dose, could influence treatment response or patient survival.

Rationale and design of a phase II trial of pyrotinib in combination with nab-paclitaxel as adjuvant therapy for N0/N1mi, HER2 + early breast cancer (PHAEDRA).

BACKGROUND: The de-escalation treatment in patients with low-risk HER2-positive early breast cancer (eBC) is an attractive strategy to avoid unnecessary treatment and improve the quality of life of patients. Pyrotinib, a novel irreversible pan-HER2 tyrosine kinase inhibitor (TKI), has shown efficacy in patients with advanced HER2-positive breast cancer. Meanwhile, nanoparticle albumin-bound (nab)-paclitaxel reveals survival benefit over solvent-based paclitaxel and eliminates the toxicities associated with the solvent. However, the efficacy and safety of pyrotinib in combination with nab-paclitaxel as adjuvant therapy for low-risk HER2 + eBC patients have not been evaluated. METHODS: This is a multicenter, open-label, single-arm phase II study. A sample size of 261 patients with tumor ≤ 3 cm, lymph node-negative (N0) or micrometastatic (N1mi), HER2 + breast cancer will be recruited. Eligible patients will receive nab-paclitaxel 260 mg/m2 once every 3 weeks for 12 weeks and pyrotinib 400 mg once daily for one year. The primary endpoint is invasive disease-free survival. A sub-study will be conducted to investigate different prophylactic strategies for diarrhea, which is the most common adverse event of pan-HER TKIs. One hundred and twenty patients from the main study will be randomly (1:1) allocated to receive loperamide either during the first cycle (4 mg tid on days 1-7, then 4 mg bid on days 8-21) or the first 2 cycles (4 mg tid on days 1-7, then 4 mg bid on days 8-42). The primary endpoint of the sub-study is the incidence of grade ≥ 3 diarrhea. DISCUSSION: This is the first prospective study of pyrotinib in combination with nab-paclitaxel as adjuvant therapy for patients with low-risk HER2-positive eBC. It would probably provide robust evidence for de-escalating strategy of HER2-positive eBC and appropriate management for pyrotinib-related diarrhea. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04659499 . Registered on December 9, 2020.

Ecotoxicological Impact of the Marine Toxin Palytoxin on the Micro-Crustacean Artemia franciscana.

Palytoxin (PLTX) is a highly toxic polyether identified in various marine organisms, such as Palythoa soft corals, Ostreopsis dinoflagellates, and Trichodesmium cyanobacteria. In addition to adverse effects in humans, negative impacts on different marine organisms have been often described during Ostreopsis blooms and the concomitant presence of PLTX and its analogues. Considering the increasing frequency of Ostreopsis blooms due to global warming, PLTX was investigated for its effects on Artemia franciscana, a crustacean commonly used as a model organism for ecotoxicological studies. At concentrations comparable to those detected in culture media of O. cf. ovata (1.0-10.0 nM), PLTX significantly reduced cysts hatching and induced significant mortality of the organisms, both at larval and adult stages. Adults appeared to be the most sensitive developmental stage to PLTX: significant mortality was recorded after only 12 h of exposure to PLTX concentrations > 1.0 nM, with a 50% lethal concentration (LC50) of 2.3 nM (95% confidence interval = 1.2-4.7 nM). The toxic effects of PLTX toward A. franciscana adults seem to involve oxidative stress induction. Indeed, the toxin significantly increased ROS levels and altered the activity of the major antioxidant enzymes, in particular catalase and peroxidase, and marginally glutathione-S-transferase and superoxide dismutase. On the whole, these results indicate that environmentally relevant concentrations of PLTX could have a negative effect on Artemia franciscana population, suggesting its potential ecotoxicological impact at the marine level.

Pyrotinib treatment enhances the radiosensitivity in HER2-positive brain metastatic breast cancer patients.

Brain metastasis is a common cause of death in HER2-positive breast cancer patients. Currently, it is mainly treated by whole-brain radiotherapy. Pyrotinib is an irreversible pan-ErbB inhibitor, which has demonstrated promising tumor-suppressing activity and acceptable tolerance in previous phase trials. In the present study, we evaluated the efficacy of pyrotinib on HER2-positive brain metastatic breast cancer patients treated with whole-brain radiotherapy. A total of 20 such patients were separated into pyrotinib plus capecitabine and capecitabine-only groups in a 1:1 ratio. All patients met either the primary or secondary endpoints. Oral admission of pyrotinib together with radiotherapy can significantly increase the overall response rate, progression-free survival, time to progression and duration of response of HER2+ brain metastatic breast cancer patients, without causing extra adverse events. In addition, pyrotinib can enhance the radiosensitivity of in-vitro cultured HER2+ breast cancer cell lines. The outcome of our study suggests that pyrotinib might be an effective medication to enhance the tumor radiosensitivity of HER2-positive brain metastatic breast cancer patients.

AZD3759 enhances radiation effects in non-small-cell lung cancer by a synergistic blockade of epidermal growth factor receptor and Janus kinase-1.

AZD3759 is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) on the basis of gefitinib and has been proven to enter the central nervous system. Although the promising antitumor effects of AZD3759 on non-small cell lung cancer (NSCLC) have been demonstrated in clinical trials, the regulatory effects of this inhibitor on the antitumor efficacy of radiation (RA) are unclear. The present study aimed to compare the effects of AZD3759 and osimertinib on RA efficacy in NSCLC and explore the potential mechanism of action of AZD3759. We found that the survival in RA-treated NSCLC cells was significantly decreased by treatment with 500 nM AZD3759 and osimertinib at the RA dosage of 8 Gy. The apoptotic rate, cell cycle arrest, and DNA damage in RA-treated NSCLC cells and brain metastasis in RA-treated xenograft nude mice were significantly enhanced by the co-administration of AZD3759 and osimertinib, respectively. In addition, AZD3759 showed a significantly stronger efficacy than osimertinib did. Mechanistically, the receptor tyrosine kinase signaling antibody array revealed that Janus kinase-1 (JAK1) was specifically inhibited by AZD3759, but not by osimertinib. The effects of AZD3759 on RA efficacy in PC-9 cells and in a brain metastasis animal model were significantly abolished by the overexpression of JAK1. Collectively, our results suggested that AZD3759 promoted RA antitumor effects in NSCLC by synergistic blockade of EGFR and JAK1.

Complete remission in leptomeningeal metastasis of NSCLC with rare EGFR-SEPT14 fusion treated with osimertinib combined with intrathecal chemotherapy with pemetrexed.

Leptomeningeal metastasis (LM) is one of the most serious complications of non-small cell lung cancer (NSCLC) without standard treatment guidelines and is always accompanied by poor prognosis. Identifying the types of gene mutations is essential to improve the outcome, and an increasing number of rare epidermal growth factor receptor (EGFR) mutations are revealed by next-generation sequencing (NGS). Here, we describe a case of a 56-year-old man who was diagnosed with lung adenocarcinoma and received thoracoscopic resection in May 2015. One year later, LM was confirmed by positive cerebrospinal fluid cytology. Given the existence of EGFR exon 19 deletions, erlotinib was implemented and achieved a short response for 10 months. Then the systemic therapy was changed to osimertinib and obtained clinical remission for 25 months. Owing to the resurgence of violent headache, retching and vomiting, NGS of cerebrospinal fluid was performed and two rare EGFR-SEPT14 fusions were found. Osimertinib combined bevacizumab, chemotherapy (carboplatin and abraxane) and dacomitinib were implemented in turn but ineffective. Thus, osimertinib combined intrathecal chemotherapy with pemetrexed were carried out and gained a complete remission of neurologic symptoms, stable lesions and long-term survival without notable side effects. This study presented the first case of NSCLC-LM harboring particular EGFR-SEPT14 fusions, who showed a durable response to osimertinib and intrathecal pemetrexed, providing a potential therapeutic option for NSCLC-LM patients with this particular mutation.

Pyrotinib in Patients with HER2-Amplified Advanced Non-Small Cell Lung Cancer: A Prospective, Multicenter, Single-Arm Trial.

PURPOSE: In this study, we aimed to evaluate the efficacy and safety of pyrotinib, a pan-HER inhibitor, in patients with HER2-amplified non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: In this prospective, multicenter, single-arm trial (ChiCTR1800020262), patients with advanced NSCLC with HER2 amplification, as determined by next-generation sequencing, were enrolled and administered pyrotinib orally at 400 mg per day. The primary endpoint was 6-month progression-free survival (PFS) rate. Other endpoints included objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety. RESULTS: The enrolled cohort included 27 patients with HER2 amplification. The 6-month PFS rate was 51.9% [95% confidence interval (CI), 34.0-69.3]. The median PFS (mPFS) was 6.3 months (95% CI, 3.0-9.6 months), and median OS was 12.5 months (95% CI, 8.2-16.8 months). Pyrotinib elicited a confirmed ORR of 22.2% (95% CI, 10.6%-40.8%). Patients administered pyrotinib as first-line treatment achieved an mPFS of 12.4 months. Moreover, 30.8% of the patients who had progressed on EGFR tyrosine kinase inhibitor (TKI) responded to pyrotinib. Patients with brain metastases had an ORR of 40%. Treatment-related adverse events (TRAE) occurred in all patients (grade 3, 22.2%), but no grade 4 or higher TRAEs were documented. Diarrhea was the most frequent TRAE (all, 92.6%; grade 3, 7.4%). Loss of HER2 amplification was detected upon disease progression. CONCLUSIONS: Pyrotinib provided antitumor efficacy with a manageable safety profile in HER2-amplified patients with NSCLC.

The natural product berberine synergizes with osimertinib preferentially against MET-amplified osimertinib-resistant lung cancer via direct MET inhibition.

Berberine is a natural product that has long been used in traditional Chinese medicine due to its antimicrobial, anti-inflammatory and metabolism-regulatory properties. Osimertinib is the first third-generation EGFR-tyrosine kinase inhibitor (TKI) approved for the treatment of non-small cell lung cancer (NSCLC) with activating EGFR mutations and those resistant to earlier generation EGFR-TKIs due to a T790M mutation. However, emergence of acquired resistance to osimertinib limits its long-term efficacy in the clinic. One known mechanism of acquired resistance to osimertinib and other EGFR-TKIs is MET (c-MET) gene amplification. Here, we report that berberine, when combined with osimertinib, synergistically and selectively decreased the survival of several MET-amplified osimertinib-resistant EGFR mutant NSCLC cell lines with enhanced induction of apoptosis likely through Bim elevation and Mcl-1 reduction. Importantly, this combination effectively enhanced suppressive effect on the growth of MET-amplified osimertinib-resistant xenografts in nude mice and was well tolerated. Molecular modeling showed that berberine was able to bind to the kinase domain of non-phosphorylated MET, occupy the front of the binding pocket, and interact with the activation loop, in a similar way as other known MET inhibitors do. MET kinase assay showed clear concentration-dependent inhibitory effects of berberine against MET activity, confirming its kinase inhibitory activity. These findings collectively suggest that berberine can act as a naturally-existing MET inhibitor to synergize with osimertinib in overcoming osimertinib acquired resistance caused by MET amplification.

INSIGHT 2: a phase II study of tepotinib plus osimertinib in MET-amplified NSCLC and first-line osimertinib resistance.

MET amplification (METamp), a mechanism of acquired resistance to EGFR tyrosine kinase inhibitors, occurs in up to 30% of patients with non-small-cell lung cancer (NSCLC) progressing on first-line osimertinib. Combining osimertinib with a MET inhibitor, such as tepotinib, an oral, highly selective, potent MET tyrosine kinase inhibitor, may overcome METamp-driven resistance. INSIGHT 2 (NCT03940703), an international, open-label, multicenter phase II trial, assesses tepotinib plus osimertinib in patients with advanced/metastatic EGFR-mutant NSCLC and acquired resistance to first-line osimertinib and METamp, determined centrally by fluorescence in situ hybridization (gene copy number ≥5 and/or MET/CEP7 ≥2) at time of progression. Patients will receive tepotinib 500 mg (450 mg active moiety) plus osimertinib 80 mg once-a-day. The primary end point is objective response, and secondary end points include duration of response, progression-free survival, overall survival and safety. Trial registration number: NCT03940703 (clinicaltrials.gov).

Osimertinib is used to treat a type of lung cancer that has specific changes (mutations) in a gene called EGFR. Although tumors will usually shrink (respond) during treatment with osimertinib, they can stop responding, or become resistant, to osimertinib. A common cause of resistance is 'MET amplification', which describes when extra copies of a gene called MET are present. Lung cancer that is resistant to osimertinib due to MET amplification could be treated by combining osimertinib with a treatment that blocks MET, such as tepotinib. INSIGHT 2 is an ongoing study that is designed to learn about the effects and safety of tepotinib combined with osimertinib, in patients with lung cancer that has stopped responding to osimertinib because of MET amplification. A plain language version of this article is available and is published alongside the paper online: www.futuremedicine.com/doi/suppl/10.2217/fon-2021-1406.

Carcinomatosis under control by osimertinib in EGFR and TP53 mutated lung adenocarcinoma.

INTRODUCTION: Approximately 25%-30% of patients with non-small cell lung cancer (NSCLC) develop central nervous system (CNS) metastases during the course of the disease; this percentage is higher in patients with epidermal growth factor receptor (EGFR) mutations. Leptomeningeal metastases, infrequent in the advanced setting, have a particularly dismal prognosis. Osimertinib, a third-generation EGFR inhibitor, can provide effective and durable response in this setting. CASE DESCRIPTION: We present a 62-year-old man with progressive vomiting, headache, short-term memory impairment, and left lower limb hyposthenia. Computed tomography (CT) showed bilateral lung nodules, multiple lymphadenopathies, liver and bone metastases, and CNS and leptomeningeal dissemination, including multiple parenchymal nodules located at supra- and infratentorial brain. Bone needle biopsy documented TTF1+ lung adenocarcinoma. Whole brain radiotherapy (WBRT) and symptomatic treatments were started. Next-generation sequencing reported deletion of exon 19 of EGFR and mutation 8 of TP53. Osimertinib 80 mg was promptly started and WBRT interrupted. Some days after the patient experienced repetitive seizures and neurologic worsening, antiepileptic drugs and dexamethasone were implemented, with gradual improvement. Radiologic evaluation, including brain MRI and thorax-abdominal CT, showed partial response on CNS as well as extracranial sites, which was sustained. CONCLUSIONS: First-line treatment with osimertinib can be safe and effective in EGFR-mutated NSCLC even in presence of multiple negative predictive factors (poor Performance Status, diffuse leptomeningeal involvement, TP53 comutation), suggesting that deferring local treatments can be feasible in this setting, allowing the patient to maintain a good quality of life.

RGFP966 is protective against lipopolysaccharide-induced depressive-like behaviors in mice by inhibiting neuroinflammation and microglial activation.

Depression is a prevalent mental disorder. However, its pathophysiological mechanism has still remained elusive, and a limited number of effective treatments have been presented. Recent studies have shown that neuroinflammation and microglial activation are involved in the pathogenesis of depression. Histone deacetylase 3 (HDAC3) has neurotoxic effects on several neuropathological conditions. The inhibition of HDAC3 has been reported to induce anti-inflammatory and antioxidant effects. RGFP966 is a highly selective inhibitor of HDAC3. This study aimed to investigate the antidepressant effect of RGFP966 on lipopolysaccharide (LPS)-induced depressive-like behaviors in mice and to explore its possible mechanism. Adult male C57BL/6J mice were utilized in this study. The LPS and RGFP966 were injected intraperitoneally daily for 5 days. The behavior tests were performed to elucidate the depression-like behaviors. Western blot, ELISA and immunofluorescence staining were used to study the HDAC3/TLR4/NLRP3 pathway-related proteins. The results of behavioral tests showed that RGFP966 could improve the LPS-induced depressive-like behaviors in mice. The results of Western blotting showed that RGFP966 treatment downregulated the expression levels of toll-like receptor 4 (TLR4), nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3), caspase-1, and interleukin-1ß (IL-1ß) (P < 0.05). Furthermore, the results of immunofluorescence staining showed that RGFP966 treatment inhibited microglial activation in the hippocampus of mice (P < 0.01). These findings suggested that RGFP966 could effectively ameliorate LPS-induced depressive-like behaviors in mice by inhibiting neuroinflammation and microglial activation. The anti-inflammatory mechanism of RGFP966 might be related to the inhibition of the HDAC3/TLR4/NLRP3 signaling pathway. Therefore, inhibition of HDAC3 using RGFP966 could serve as a potential treatment strategy for depression.