Treatment of Relapsed and Refractory ALK-Positive Anaplastic Large Cell Lymphoma With ALK-Specific Tyrosine Kinase Inhibitor in Children: A Case Series.

Relapsed and refractory ALK-positive anaplastic large cell lymphoma (ALCL) has a poor prognosis. In this report, we present 3 relapsed/refractory pediatric ALCL patients, 1 of these with central nervous system involvement. All 3 patients were treated with ALK inhibitor and achieved complete response. Both crizotinib and alectinib have shown significant activity in pediatric patients with refractory ALK-positive ALCL.

Co-delivery of sorafenib and crizotinib encapsulated with polymeric nanoparticles for the treatment of in vivo lung cancer animal model.

To treat various cancers, including lung cancer, chemotherapy requires the systematic administering of chemotherapy. The chemotherapeutic effectiveness of anticancer drugs has been enhanced by polymer nanoparticles (NPs), according to new findings. As an outcome, we have developed biodegradable triblock poly(ethylene glycol)-poly(ε-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) polymeric NPs for the co-delivery of sorafenib (SORA) and crizotinib (CRIZ) and investigated their effect on lung cancer by in vitro and in vivo. There is little polydispersity in the SORA-CRIZ@NPs, an average size of 30.45 ± 2.89 nm range. A steady release of SORA and CRIZ was observed, with no burst impact. The apoptosis rate of SORA-CRIZ@NPs was greater than that of free drugs in 4T1 and A549 cells. Further, in vitro cytotoxicity of the polymeric NPs loaded with potential anticancer drugs was more quickly absorbed by cancer cells. On the other hand, compared to free drugs (SORA + CRIZ), SORA + CRIZ@NPs showed a substantial reduction of tumor development, longer survival rate, and a lowered side effect when delivered intravenously to nude mice xenograft model with 4T1 cancer cells. TUNEL positivity was also increased in tumor cells treated with SORA-CRIZ@NPs, demonstrating the therapeutic effectiveness. SORA-CRIZ@NPs might be used to treat lung cancer soon, based on the results from our new findings.

Population pharmacokinetic analysis of crizotinib in children with progressive/recurrent high-grade and diffuse intrinsic pontine gliomas.

PURPOSE: Crizotinib, a potent oral tyrosine kinase inhibitor, was evaluated in combination with dasatinib in a phase 1 trial (NCT01644773) in children with progressive or recurrent high-grade and diffuse intrinsic pontine gliomas (HGG and DIPG). This study aimed to characterize the pharmacokinetics of crizotinib in this population and identify significant covariates. METHODS: Patients (N = 36, age range 2.9-21.3 years) were treated orally once or twice-daily with 100-215 mg/m2 crizotinib and 50-65 mg/m2 dasatinib. Pharmacokinetic studies were performed for crizotinib alone after the first dose and at steady state, and for the drug combination at steady state. Crizotinib plasma concentrations were measured using a validated LC-MS/MS method. Population modeling was performed (Monolix) and the impact of factors including patient demographics and co-medications were investigated on crizotinib pharmacokinetics. RESULTS: Crizotinib concentrations were described with a linear two-compartment model and absorption lag time. Concomitant dasatinib and overweight/obese status significantly influenced crizotinib pharmacokinetics, resulting in clinically relevant impact (> 20%) on drug exposure. Crizotinib mean apparent clearance (CL/F) was 66.7 L/h/m2 after single-dose and decreased to 26.5 L/h/m2 at steady state when given alone, but not when combined with dasatinib (mean 60.8 L/h/m2). Overweight/obese patients exhibited lower crizotinib CL/F and apparent volume V1/F (mean 46.2 L/h/m2 and 73.3 L/m2) compared to other patients (mean 75.5 L/h/m2 and 119.3 L/m2, p < 0.001). CONCLUSION: A potential pharmacokinetic interaction was observed between crizotinib and dasatinib in children with HGG and DIPG. Further, crizotinib exposure was significantly higher in overweight/obese patients, who may require a dosing adjustment.

Combination treatment with trastuzumab and crizotinib in metastatic gastric cancer harboring Her-2 amplification and c-MET amplification: A case report.

RATIONALE: Metastatic gastric cancer patients with poor eastern cooperative oncology group performance status (PS) (≥3) were lack of effective anti-tumor strategies. They always lived with poor PS, severe and multiple symptoms, and usually resulted in extremely limited survival time. Herein, we reported a patient diagnosed with gastric cancer metastasized to multiple bones, along with lymphangitis carcinomatosa in lungs, harboring Her-2 and c-MET amplification with poor PS, positively responded to combinational therapy with trastuzumab and crizotinib. PATIENT CONCERNS: The patient complained of persistent cough and fatigue for 2 months, otherwise, she denied smoking, alcohol history, or any other medical or family history. DIAGNOSIS: With the biopsy results from gastroscopy, as well as computer tomography for chest and abdomen, the patient was diagnosed as gastric adenocarcinoma, with metastasis on lungs, left adrenal gland, retroperitoneal lymph nodes, and multiple bones. INTERVENTIONS: Because of the poor PS (PS = 3), as well as Her-2 and c-MET amplification, the patient received combination treatment with trastuzumab and crizotinib as salvage strategy. OUTCOMES: After 2 months' exposure of trastuzumab and crizotinib, symptoms including persistent cough, and chest distress were alleviated significantly. Simultaneously, chest computer tomography showed significant dissipation of lymphangitis carcinomatosa, as well as apparent reduction of pleural effusion. No adverse reactions including nausea, vomiting, diarrhea, or hypertension was observed during the following 2 months. LESSONS: The present case suggested that combinational therapy with trastuzumab and crizotinib might be effective in metastatic gastric cancer patients harboring Her-2 and c-MET amplification, even with a poor PS. It was also implied that gene sequencing might be valuable, especially in patients with limited treatment strategies.

[Whole-process Management of Treatment of Advanced ALK Positive Non-small Cell Lung Cancer: A Case Report].

BACKGROUND: Anaplastic lymphoma kinase (ALK) is an important therapeutic target for advanced non-small cell lung cancer (NSCLC). In recent years, with the emergence of several ALK tyrosine kinase inhibitors (TKI), the overall survival (OS) of ALK fusion positive patients is gradually extended. This paper reports the treatment of a late stage non-small cell lung cancer (NSCLC) patient with ALK fusion positive for more than 5 years, and analyzes the treatment process and effect evaluation, so as to provide experience for the follow-up treatment of patients. METHODS: The diagnosis and treatment process of a patient with advanced ALK fusion mutation positive lung cancer admitted to the third ward of Department of oncology, Chifeng hospital, Inner Mongolia on July 3, 2015 was retrospectively analyzed. RESULTS: A 42 years old male patient was admitted to our department on July 3, 2015 for "intermittent cough, chest tightness for 2 months, diagnosed with lung adenocarcinoma for 1 day". Imaging examination showed a space occupying lesion in the left lower lobe of the lung, accompanied by mediastinal lymphadenopathy and left encapsulated pleural effusion. Bronchoscopic pathology showed non-small cell carcinoma, and adenocarcinoma was tentatively suggested. DIAGNOSIS: left lower lobe adenocarcinoma T1bN2M1a stage IV. Fluorescence in situ hybridization (FISH) indicated the translocation of ALK (2p23) chromosome. After 2 cycles of docetaxel+cisplatin (DP) regimens chemotherapy, disease progression occurred, so we used 6 cycles of pemetrexed+carboplatin to apply combination chemotherapy, 4 cycles of pemetrexed monotherapy were used after that. The efficacy evaluation: PR. On April 9, 2016, the patient was treated with crizotinib. In August 2019, multiple intracranial metastases were found and whole brain radiotherapy was given. Since September 4, 2019, oral administration of nsatinib has been carried out. As of March 1, 2021, the patients were followed up well. CONCLUSIONS: The advanced ALK fusion positive lung adenocarcinoma patients, though the first-line and the second-line chemotherapy, and the follwing application of ALK-TKI treatment, has procured a total OS has reached 68 months, and the current follow-up is good.

Characteristics of central nervous system progression in non-small cell lung cancer treated with crizotinib or alectinib.

BACKGROUND: Most patients treated with anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors for ALK-positive non-small cell lung cancer (NSCLC) develop resistance, leading to metastasis, with progression to the central nervous system (CNS) being a primary concern. Although alectinib has better CNS penetration than crizotinib, patients treated with alectinib also develop CNS progression. CNS metastases more likely occurs during crizotinib treatment due to less blood-brain barrier (BBB) penetration capability than alectinib. CNS progression pattern may be different during crizotinib and alecitinib treatment. Understanding the characteristics of CNS progression is important for developing treatment strategies. AIMS: We compared the clinical-radiographic characteristics of CNS metastases among patients undergoing crizotinib and alectinib treatment for ALK-positive NSCLCs. METHODS AND RESULTS: We retrospectively analyzed the radiographic and clinical characteristics of CNS progression in ALK-positive NSCLC patients treated with crizotinib or alectinib at our hospital between July 2011 and May 2020. CNS and systemic tumor progression were evaluated using computed tomography or magnetic resonance imaging. Fifty-three and 65 patients were treated with crizotinib and alectinib, respectively. Baseline CNS metastasis was observed in 18 and 27 patients in the crizotinib and alectinib groups, respectively. Among the patients in the crizotinib and alectinib groups who developed disease progression, 15/49 (30.6%) and 9/44 (20.5%) had CNS progression, respectively (P = .344). Intra-CNS progression-free survival was significantly longer in the alectinib group than in the crizotinib group (median: 14.0 vs 5.6 months, P = .042). The number of CNS metastases sized ≥3 cm, rate of peritumoral brain edema, and the second progression pattern after treatment continuation was not significantly different between the groups. CONCLUSION: We observed no significant difference in the clinical-radiographic characteristics of CNS progression between patients undergoing crizotinib and alectinib treatments. Local therapy, including stereotactic radiosurgery, for CNS progression may be suitable and important following alectinib and crizotinib treatment.

A retrospective study of alectinib versus ceritinib in patients with advanced non-small-cell lung cancer of anaplastic lymphoma kinase fusion in whom crizotinib treatment failed.

BACKGROUND: Crizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion. Failure of crizotinib treatment frequently involves drug intolerance or resistance. Comparison of using second-generation ALK inhibitors in this setting remains lacking. METHODS: Sixty-five ALK-positive advanced NSCLC patients receiving second-generation ALK inhibitors following treatment failure of crizotinib were retrospectively analyzed for the therapeutic efficacy. RESULTS: Forty-three (66.2%) and 22 (33.8%) patients received alectinib and ceritinib, respectively. Comparing alectinib to ceritinib treatment: the 12-month progression-free survival (PFS) rate (61.0% [95% confidence interval, 47.1 to 78.9%] vs. 54.5% [95% CI, 37.3 to 79.9%]); the hazard ratio (HR) for disease progression or death, 0.61 (95% CI, 0.31-1.17; p = 0.135). Multivariate Cox regression showed ECOG PS (0-1 vs. 2-3 HR 0.09 [95% CI, 0.02-0.33]; p < 0.001) and cause of crizotinib treatment failure (resistance vs. intolerance HR 2.75 [95% CI, 1.26-5.99]; p = 0.011) were the independent predictors for the PFS of second-generation ALK inhibitors. Treatment of alectinib, compared to ceritinib, was associated with a lower incidence of CNS progression (cause-specific HR, 0.10; 95% CI 0.01-0.78; p = 0.029) and a higher efficacy in patients whose cause of crizotinib treatment failure was intolerance (HR 0.29 [95% CI, 0.08-1.06]; p = 0.050). The most commonly noted adverse events were elevated AST/ALT in 10 (23.3%) patients treated with alectinib and diarrhea in 8 (36.4%) patients treated with ceritinib. CONCLUSION: Second-generation ALK inhibitors in crizotinib-treated patients showed a satifactory efficacy. Alectinib treatment demonstrated a CNS protection activity and a higher PFS in selected patients failing crizotinib treatment.

Responses to crizotinib and cabozantinib in patient with lung adenocarcinoma harboring mesenchymal-epithelial transition factor exon 14 skipping mutation: A case report.

RATIONALE: Lung cancer is a leading cause of cancer-related mortality worldwide. Currently, targeted therapy has proved highly efficient in the treatment of advanced non-small cell lung cancer (NSCLC). Mesenchymal-epithelial transition factor (MET) is considered a validated molecular target in NSCLC. Given the low incidence of MET exon 14 skipping mutation, the planning of precision treatment for patients is a clinical problem that needs to be solved. In this report, we present a MET-positive case that benefited from crizotinib and cabozantinib treatment. PATIENT CONCERNS: A 77-year-old patient was diagnosed with lung adenocarcinoma in our hospital. Positron emission tomography-computed tomography (PET-CT) showed a right upper lobe mass (58 × 56 mm, SUVmax 15.6), right hilar enlarged lymph nodes, and multiple bone and left adrenal metastases (c-T3N1M1c). DIAGNOSES: MET exon 14 mutation (exon14, c.2888-1G>C) was examined using the lung puncture sample by next generation sequencing. Therefore, the patient was diagnosed with late-stage lung adenocarcinoma with MET exon14 skipping gene mutation. INTERVENTIONS: Crizotinib was given as the first-line treatment from August 2019. Considering the resistance of crizotinib, cabozantinib was given for second-line treatment. OUTCOMES: Crizotinib was administered (250 mg bid) for 8 months, and her disease achieved partial regression (PR) and progression-free survival (PFS), which lasted for 8 months. The patient also reached PR after the second-line treatment with cabozantinib, and is currently under follow-up, with an overall survival (OS) of >12 months. LESSONS: As MET exon 14 skipping mutation is rare in clinical practices, MET-TKIs (tyrosine kinase inhibitors) treatment can boost curative effects and improve prognosis of patients with advanced lung adenocarcinoma. This case report supports a rationale for the treatment of lung adenocarcinoma patients with a MET exon 14 skipping mutation and provides alternative treatment options for these types of NSCLC patients.

A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial.

BACKGROUND: MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC. METHODS: We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057. FINDINGS: Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6-12) than in the sunitinib group (5·6 months, 3-7; hazard ratio for progression or death 0·60, 0·37-0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group. INTERPRETATION: Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC. FUNDING: National Institutes of Health and National Cancer Institute.

Sequential therapy of crizotinib followed by alectinib for non-small cell lung cancer harbouring anaplastic lymphoma kinase rearrangement (WJOG9516L): A multicenter retrospective cohort study.

BACKGROUND: The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited. METHODS: We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group. RESULTS: Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001). CONCLUSION: The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.

Revisiting a lower starting dose of alectinib in ALK-Positive non-small cell lung cancer.

We present here a case of ALK-positive lung adenocarcinoma that has been started on Alectinib. Treatment has been initiated at the recommended initial dose, but it subsequently required a dose adjustment following adverse drug events. Alectinib is a second-generation, CNS-active, tyrosine kinase inhibitor used in the treatment of ALK-positive non-small cell lung cancer. Its efficacy as a first-line treatment and as a second-line agent after Crizotinib has been proven across several trials both in terms of overall response rate and progression-free survival. The use of Alectinib is associated with side effects that occasionally lead to treatment discontinuation, interruption, or dose adjustment. Several studies have used two starting doses - 300 mg and 600 mg twice daily - across different populations and have consistently shown efficacy of Alectinib for both treatment doses. Results of these studies have also revealed that body weight, rather than race, affect the pharmacokinetics of Alectinib. Randomized trials have shown that the 600 mg dose is associated with more grade ≥3 adverse events and more changes in treatment in contrast to the 300 mg dose. A lower dose of Alectinib may limit treatment disruptions and dose reductions particularly for specific patient populations-particularly those with a lower body weight.

Proteasome Inhibition Overcomes ALK-TKI Resistance in ALK-Rearranged/TP53-Mutant NSCLC via Noxa Expression.

PURPOSE: In ALK-rearranged non-small cell lung cancer (NSCLC), impacts of concomitant genetic alterations on targeted therapies with ALK-tyrosine kinase inhibitors (ALK-TKI) are not yet well understood. Here, we investigated genetic alterations related to ALK-TKI resistance using clinico-genomic data and explored effective therapies to overcome the resistance in preclinical models through the identification of underlying molecular mechanisms. EXPERIMENTAL DESIGN: We used integrated clinical and next-generation sequencing data generated in a nationwide lung cancer genome screening project (LC-SCRUM-Japan). ALK-rearranged NSCLC cell lines expressing wild-type or mutant TP53 were used to evaluate cellular apoptosis induced by ALK-TKIs. RESULTS: In 90 patients with ALK-rearranged NSCLC who were treated with a selective ALK-TKI, alectinib, TP53 comutated patients showed significantly worse progression-free survival (PFS) than TP53 wild-type patients [median PFS, 11.7 months (95% confidence interval, CI, 6.3-not reached, NR) vs. NR (23.6-NR); P = 0.0008; HR, 0.33 (95% CI, 0.17-0.65)]. ALK-rearranged NSCLC cell lines that lost p53 function were resistant to alectinib-induced apoptosis, but a proteasome inhibitior, ixazomib, markedly induced apoptosis in the alectinib-treated cells by increasing the expression of a proapoptotic protein, Noxa, which bound to an antiapoptotic protein, Mcl-1. In subcutaneous tumor models, combination of ixazomib and alectinib prominently induced tumor regression and apoptosis even though the tumors were generated from ALK-rearranged NSCLC cells with nonfunctional p53. CONCLUSIONS: These clinical and preclinical results indicate concomitant TP53 mutations reduce the efficacy of alectinib for ALK-rearranged NSCLC and the combined use of a proteasome inhibitor with alectinib is a promising therapy for ALK-rearranged/TP53-mutated NSCLC.

The effect of metformin in EML4-ALK+ lung cancer alone and in combination with crizotinib in cell and rodent models.

Cell based studies have suggested that the diabetes drug metformin may combine with the anaplastic lymphoma kinase receptor (ALK) inhibitor crizotinib to increase ALK positive lung cancer cell killing and overcome crizotinib resistance. We therefore tested metformin alone and in combination with crizotinib in vivo, by employing a xenograft mouse model of ALK positive lung cancer. We found that 14 days of daily oral metformin (100 mg/kg) alone had a moderate but statistically significant effect on tumour growth suppression, but in combination with crizotinib, produced no greater tumour suppression than crizotinib (25 mg/kg) alone. We also reassessed the effect of metformin on EML4-ALK positive lung cancer (H3122) cell viability. Although metformin alone did have a moderate effect on cell viability (30% suppression) this was only at a clinically irrelevant concentration (5 mM) and there was no additive effect with cytotoxic concentrations of crizotinib. Moreover, metformin did not overcome crizotinib resistance in our resistant cells. Nevertheless, we were able to show that metformin induces a G1-cell cycle arrest and apoptosis alone and in combination with crizotinib. Also, consistent with earlier work, the addition of insulin-like growth factor-1 (IGF-1) to EML4-ALK positive cancer cells reduced cell killing by crizotinib. We therefore hypothesised that the effect of metformin in vivo was not due to direct cytotoxicity on cancer cells, but by modulation of IGF-1 expression. We therefore measured levels of IGF-1 in plasma taken from mice treated with metformin, but found no difference between the drug treatment and control groups. We further hypothesised that the effect of metformin could be due to modulation of thrombospondin 1 (TSP-1), which metformin has been proposed to regulatein vivo, but again we found no difference between the experimental groups. Finally, we investigated the potential for liver and kidney toxicity, as well as CYP3A based interactions, from the combination of metformin with crizotinib.

Crizotinib induced antitumor activity and synergized with chemotherapy and hormonal drugs in breast cancer cells via downregulating MET and estrogen receptor levels.

MET is a receptor tyrosine kinase known to drive neoplastic transformation and aggressive tumor phenotypes. Crizotinib is an oral multi-targeted tyrosine kinase inhibitor of MET, ALK, RON, and ROS1 kinases. In this study, the anticancer effects of crizotinib on breast cancer cells were investigated in vitro along with the molecular mechanisms associated with these effects. Besides, the antiproliferative effects of crizotinib in combination with chemotherapy, hormonal drugs, and targeted agents were examined. Results showed that crizotinib produced dose-dependent antiproliferative effects in BT-474 and SK-BR-3 breast cancer cells with IC50 values of 1.7 µM and 5.2 µM, respectively. Crizotinib inhibited colony formation of BT-474 cells at low micromolar concentrations (1-5 µM). Immunofluorescence and Western blotting indicated that crizotinib reduced total levels of MET and estrogen receptor (ERα) in BT-474 cells. Also, crizotinib reduced the levels of phosphorylated (active) MET and HER2 in BT-474 cells. The combined treatment of crizotinib with doxorubicin and paclitaxel resulted in synergistic growth inhibition of BT-474 cells with combination index values of 0.46 and 0.35, respectively. Synergy was also observed with the combination of crizotinib with the hormonal drugs 4-hydroxytamoxifen and fulvestrant in BT-474 cells. Alternatively, the combination of crizotinib with lapatinib produced antagonistic antiproliferative effects in both BT-474 and SK-BR-3 cells. Collectively, these findings demonstrate the anticancer effects of crizotinib in breast cancer cells and reveal ERα as a potential therapeutic target of the drug apart from its classical kinase inhibitory activity. Crizotinib could be an appealing option in combination with chemotherapy or hormonal drugs for the management of breast cancer.

Pharmacoenhancement of Low Crizotinib Plasma Concentrations in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer using the CYP3A Inhibitor Cobicistat.

The inhibitor of anaplastic lymphoma kinase (ALK) crizotinib significantly increases survival in patients with ALK-positive non-small cell lung cancer (NSCLC). When evaluating crizotinib pharmacokinetics (PKs) in patients taking the standard flat oral dose of 250 mg b.i.d., interindividual PK variability is substantial and patient survival is lower in the quartile with the lowest steady-state trough plasma concentrations (Cmin,ss ), suggesting that concentrations should be monitored and doses individualized. We investigated whether the CYP3A inhibitor cobicistat increases Cmin,ss of the CYP3A substrate crizotinib in patients with low exposure. Patients with ALK-positive NSCLC of our outpatient clinic treated with crizotinib were enrolled in a phase I trial (EudraCT 2016-002187-14, DRKS00012360) if crizotinib Cmin,ss was below 310 ng/mL and treated with cobicistat for 14 days. Crizotinib plasma concentration profiles were established before and after a 14-day co-administration of cobicistat to construct the area under the plasma concentration-time curve in the dosing interval from zero to 12 hours (AUC0-12 ). Patients were also monitored for adverse events by physical examination, laboratory tests, and 12-lead echocardiogram. Enrolment was prematurely stopped because of the approval of alectinib, a next-generation ALK-inhibitor with superior efficacy. In the only patient enrolled, cobicistat increased Cmin,ss from 158 ng/mL (before cobicistat) to 308 ng/mL (day 8) and 417 ng/mL (day 14 on cobicistat), concurrently the AUC0-12 increased by 78% from 2,210 ng/mL*h to 3,925 ng/mL*h. Neither safety signals nor serious adverse events occurred. Pharmacoenhancement with cobicistat as an alternative for dose individualisation for patients with NSCLC with low crizotinib exposure appears to be safe and is cost-effective and feasible.

Dose-escalation study of vemurafenib with sorafenib or crizotinib in patients with BRAF-mutated advanced cancers.

BACKGROUND: BRAF inhibitors are effective in melanoma and other cancers with BRAF mutations; however, patients ultimately develop therapeutic resistance through the activation of alternative signaling pathways such as RAF/RAS or MET. The authors hypothesized that combining the BRAF inhibitor vemurafenib with either the multikinase inhibitor sorafenib or the MET inhibitor crizotinib could overcome therapeutic resistance. METHODS: Patients with advanced cancers and BRAF mutations were enrolled in a dose-escalation study (3 + 3 design) to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of vemurafenib with sorafenib (VS) or vemurafenib with crizotinib (VC). RESULTS: In total, 38 patients (VS, n = 24; VC, n = 14) were enrolled, and melanoma was the most represented tumor type (VS, 38%; VC, 64%). In the VS arm, vemurafenib 720 mg twice daily and sorafenib 400 mg am/200 mg pm were identified as the MTDs, DLTs included grade 3 rash (n = 2) and grade 3 hypertension, and partial responses were reported in 5 patients (21%), including 2 with ovarian cancer who had received previous treatment with BRAF, MEK, or ERK inhibitors. In the VC arm, vemurafenib 720 mg twice daily and crizotinib 250 mg daily were identified as the MTDs, DLTs included grade 3 rash (n = 2), and partial responses were reported in 4 patients (29%; melanoma, n = 3; lung adenocarcinoma, n = 1) who had received previous treatment with BRAF, MEK, and/or ERK inhibitors. Optional longitudinal collection of plasma to assess dynamic changes in circulating tumor DNA demonstrated the elimination of BRAF-mutant DNA from plasma during therapy (P = .005). CONCLUSIONS: Vemurafenib combined with sorafenib or crizotinib was well tolerated with encouraging activity, including among patients who previously received treatment with BRAF, MEK, or ERK inhibitors.

Brigatinib Dose Rationale in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: Exposure-Response Analyses of Pivotal ALTA Study.

Brigatinib is a kinase inhibitor indicated for patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer who progressed on or are intolerant to crizotinib. Approval was based on results from a randomized, dose-ranging phase II study (ALK in Lung Cancer Trial of AP26113 (ALTA)). Despite an apparent dose-response relationship for efficacy in ALTA, an exposure-response relationship was not discernable using static models driven by time-averaged exposure. However, exposure-response modeling using daily time-varying area under the concentration curve as the predictor in time-to-event models predicted that increasing the dose of brigatinib (range, 30 mg once daily (q.d.) to 240 mg q.d.) would result in clinically meaningful improvements in progression-free survival (PFS), intracranial PFS, and overall survival. Grade ≥ 2 rash and amylase elevation were predicted to significantly increase with brigatinib exposure. These results provided support for a favorable benefit-risk profile with the approved dosing regimen (180 mg q.d. with 7-day lead-in at 90 mg) versus 90 mg q.d.