ABSTRACT
Antibody-drug conjugates (ADCs) are a fast-growing class of cancer drugs designed to selectively deliver cytotoxic payloads through antibody binding to cancer cells with high expression of the target antigen, thus reducing systemic exposure and minimizing off-target effects. However, ADCs are associated with various ocular adverse events (AEs) that may impact treatment administration and patient outcomes. In this review, we provide a summary of ocular AEs associated with approved and investigational ADCs, recommendations for the mitigation and management of ocular AEs, current guidelines and expert opinions, and recommendations for clinical practice. A literature search was performed, using PubMed and Google Scholar, for English-language articles published between January 1985 and January 2023 to identify studies reporting ocular AEs associated with ADC use. Search terms included generic and investigational names of all identified ADCs, and further searches were performed to identify strategies for managing ADC-associated ocular AEs. ADC-associated ocular AEs include symptoms such as blurred vision and foreign-body sensation and signs such as corneal fluorescein staining, corneal pseudomicrocysts, and conjunctivitis. Reported management strategies include ADC dose modification (eg, dose delay or reduction), cool compresses, artificial tears, topical vasoconstrictors, and topical steroids. Although ADC dose modification appears to be beneficial, the preventive and/or therapeutic benefits of the remaining interventions are unclear. Although the exact mechanisms are not fully understood, most ADC-associated ocular AEs are reversible with dose delay or dose reduction. Management of ocular AEs requires a multidisciplinary approach to minimize treatment discontinuation and optimize clinical outcomes.
ABSTRACT
BACKGROUND: Sotorasib showed anticancer activity in patients with KRAS p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non-small-cell lung cancer (NSCLC). METHODS: In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with KRAS p.G12C-mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy. RESULTS: Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in STK11, KEAP1, or TP53. CONCLUSIONS: In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Piperazines/therapeutic use , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Pyridines/therapeutic use , Pyrimidines/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/metabolism , Biomarkers/blood , Carcinoma, Non-Small-Cell Lung/genetics , Female , Humans , Lung Neoplasms/genetics , Male , Middle Aged , Mutation , Piperazines/adverse effects , Progression-Free Survival , Pyridines/adverse effects , Pyrimidines/adverse effectsABSTRACT
WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a study called CodeBreaK 100. The CodeBreaK 100 study included patients with non-small-cell lung cancer that had spread outside the lung (advanced). Lung cancer is one of the most common forms of cancer. CodeBreaK 100 specifically looked at patients with a particular change(mutation) in the KRAS gene resulting in the mutated protein called KRAS G12C. The KRAS G12C mutation can lead to development and growth of lung cancer. Patients received a treatment called sotorasib, which has accelerated approval or full approval in over 50 countries for patients with non-small-cell lung cancer with the KRAS G12C mutation. The CodeBreaK 100 study looked at whether sotorasib is a safe and effective treatment for advanced non-small-cell lung cancer. Sotorasib is designed to specifically target and lock the mutated KRAS protein in the inactive state to treat non-small-cell lung cancer. WHAT WERE THE RESULTS?: In total, 174 adults were treated with sotorasib. Treatment-related side effects were seen in 70% of patients and were severe in 21% of patients. The most common side effects included diarrhea, increased liver enzymes, nausea and tiredness. 70 (41%) patients responded to sotorasib and 144 (84%) patients had tumors that either remained stable or shrunk in size. 29 (41%) patients who responded to sotorasib responded for over 12 months. After 2 years, 9 patients with a response remained on sotorasib; there were no notable increases in tumor size or development of new tumors over this time. There were 5patients who received sotorasib for more than 2 years and continued to respond. Long-term benefit was seen for some patients. Patients also benefitted from treatment when the tumor expressed different amounts of a protein called PD-L1.In total, 33% of patients were still alive after 2 years. WHAT DO THE RESULTS MEAN?: Results show the long-term benefit of sotorasib therapy for people with advanced KRAS G12C-mutated non-small-cell lung cancer. Clinical Trial Registration: NCT03600883 (CodeBreaK 100) (ClinicalTrials.gov).
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Piperazines , Pyridines , Pyrimidines , Adult , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Language , MutationABSTRACT
BACKGROUND: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. METHODS: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. CONCLUSIONS: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Colorectal Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Mutation , Piperazines/administration & dosage , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Pyridines/administration & dosage , Pyrimidines/administration & dosage , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Neoplasms/drug therapy , Piperazines/adverse effects , Piperazines/pharmacokinetics , Proto-Oncogene Proteins p21(ras)/genetics , Pyridines/adverse effects , Pyridines/pharmacokinetics , Pyrimidines/adverse effects , Pyrimidines/pharmacokineticsABSTRACT
BACKGROUND: RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event. CONCLUSIONS: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Proto-Oncogene Proteins c-ret/antagonists & inhibitors , Pyrazoles/administration & dosage , Pyridines/administration & dosage , Adult , Aged , Aged, 80 and over , Female , Humans , Hypertension/chemically induced , Intention to Treat Analysis , Male , Middle Aged , Mutation , Progression-Free Survival , Protein Kinase Inhibitors/adverse effects , Proto-Oncogene Proteins c-ret/analysis , Proto-Oncogene Proteins c-ret/genetics , Pyrazoles/adverse effects , Pyridines/adverse effects , Transaminases/blood , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors may synergize with programmed cell death receptor-1 (PD-1) inhibitors to enhance adaptive and innate antitumor immune responses. In the phase 2 JASPER study (NCT04475939), the PARP inhibitor niraparib was evaluated in combination with the PD-1 inhibitor pembrolizumab in patients with metastatic and/or locally advanced non-small cell lung cancer (NSCLC). METHODS: Patients whose tumors had programmed cell death ligand 1 (PD-L1) tumor proportion scores (TPS) ≥50% (cohort 1) or 1%-49% (cohort 2) received first-line niraparib (200 mg once daily) plus pembrolizumab (200 mg every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR). Secondary end points included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. RESULTS: Thirty-eight patients were enrolled in cohorts 1 and 2. In cohort 1, ORR (95% confidence interval [CI]) was 56.3% (9 of 16 patients; 29.9%-80.2%); 2 of 16 patients had complete responses and 7 of 16 had partial responses (PRs). In cohort 2, ORR was 20.0% (5.7%-43.7%) with 4 of 20 PRs. In cohorts 1 and 2, the median DoR was 19.7 months (95% CI, 4.2 months to not estimable [NE]) and 9.4 months (95% CI, 4.2 months to NE), the median PFS was 8.4 months (95% CI, 3.9-22.1 months) and 4.2 months (95% CI, 2.0-6.2 months), and the median OS was NE (95% CI, 6.0 months to NE) and 7.7 months (95% CI, 4.0-12.5 months), respectively. Grade ≥3 treatment-emergent adverse events occurred in 88.2% and 85.7% of patients in cohorts 1 and 2, respectively. Safety was consistent with known profiles of single-agent niraparib and pembrolizumab. CONCLUSIONS: Niraparib plus pembrolizumab showed clinical activity in patients with advanced and/or metastatic NSCLC. LAY SUMMARY: The JASPER clinical trial studied a new combination treatment for advanced or metastatic non-small cell lung cancer (NSCLC). Pembrolizumab, a drug approved for NSCLC, was given with niraparib. Previous research showed that these 2 drugs together might work better than either drug alone. This study found that more than half of patients with high levels of a tumor marker responded to the combination, and one-fifth of patients with lower levels of the marker responded. The types of side effects from the combination were similar to side effects from both drugs alone. These results support more research on this combination.
Subject(s)
Antibodies, Monoclonal, Humanized , Carcinoma, Non-Small-Cell Lung , Indazoles , Lung Neoplasms , Piperidines , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Indazoles/adverse effects , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Piperidines/adverse effects , Poly(ADP-ribose) Polymerase Inhibitors/adverse effectsABSTRACT
Purpose Combining small-molecule inhibitors of different targets was shown to be synergistic in preclinical studies. Testing this concept in clinical trials is, however, daunting due to challenges in toxicity management and efficacy assessment. This study attempted to evaluate the safety and efficacy of vatalanib plus everolimus in patients with advanced solid tumors and explore the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies as a predictive biomarker. Patients and Methods This single-center, phase I trial containing 70 evaluable patients consisted of a dose escalation proportion based on the traditional "3 + 3" design (cohort IA and IB) and a dose expansion proportion (cohort IIA and IIB). Toxicity was evaluated using the Common Terminology Criteria of Adverse Events. Antitumor activity was assessed using the Modified Response Evaluation Criteria in Solid Tumors. Results The maximum tolerated doses were determined to be vatalanib 1250 mg once daily or 750 mg twice daily in combination with everolimus 10 mg once daily. No treatment-related death occurred. The most common toxicities were hypertriglyceridemia, hypercholesterolemia, fatigue, vomiting, nausea and diarrhea. There was no complete response. Nine patients (12.9%) had partial response (PR) and 41 (58.6%) had stable disease (SD). Significant antitumor activity was observed in neuroendocrine tumors with a disease-control rate (PR + SD) of 66.7% and other tumor types including renal cancer, melanoma, and non-small-cell lung cancer. Conclusions The combination of vatalanib and everolimus demonstrated reasonable toxicity and clinical activity. Future studies combining targeted therapies and incorporating biomarker analysis are warranted based on this phase I trial.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Everolimus/administration & dosage , Neoplasms/drug therapy , Phthalazines/administration & dosage , Protein Kinase Inhibitors/administration & dosage , Pyridines/administration & dosage , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Everolimus/adverse effects , Female , Humans , Male , Middle Aged , Phthalazines/adverse effects , Protein Kinase Inhibitors/adverse effects , Pyridines/adverse effects , Treatment Outcome , Young AdultABSTRACT
Answer questions and earn CME/CNE Advances in genomics and molecular biology have identified aberrant proteins in cancer cells that are attractive targets for cancer therapy. Because these proteins are overexpressed or dysregulated in cancer cells compared with normal cells, it was assumed that their inhibitors will be narrowly targeted and relatively nontoxic. However, this hope has not been achieved. Current targeted agents exhibit the same frequency and severity of toxicities as traditional cytotoxic agents, with the main difference being the nature of the toxic effects. Thus, the classical chemotherapy toxicities of alopecia, myelosuppression, mucositis, nausea, and vomiting have been generally replaced by vascular, dermatologic, endocrine, coagulation, immunologic, ocular, and pulmonary toxicities. These toxicities need to be recognized, prevented, and optimally managed.
Subject(s)
Antineoplastic Agents/adverse effects , Neoplasms/drug therapy , Bone Marrow Diseases/chemically induced , Cachexia/chemically induced , Diarrhea/chemically induced , Drug Eruptions/etiology , Drug Eruptions/therapy , Endocrine System Diseases/chemically induced , Exanthema/chemically induced , Heart Diseases/chemically induced , Hemorrhage/chemically induced , Humans , Hyperbilirubinemia/chemically induced , Hyperlipidemias/chemically induced , Immune System Diseases/chemically induced , Lung Diseases, Interstitial/chemically induced , Magnesium/blood , Mood Disorders/chemically induced , Peripheral Nervous System Diseases/chemically induced , Pleural Effusion/chemically induced , Thrombocytopenia/chemically induced , Venous Thromboembolism/chemically induced , Vision Disorders/chemically inducedABSTRACT
BACKGROUND: Regulatory approval of next generation sequencing (NGS) by the FDA is advancing the use of genomic-based precision medicine for the therapeutic management of cancer as standard care. Recent FDA guidance for the classification of genomic variants based on clinical evidence to aid clinicians in understanding the actionability of identified variants provided by comprehensive NGS panels has also been set forth. In this retrospective analysis, we interpreted and applied the FDA variant classification guidance to comprehensive NGS testing performed for advanced cancer patients and assessed oncologist agreement with NGS test treatment recommendations. METHODS: NGS comprehensive genomic profiling was performed in a CLIA certified lab (657 completed tests for 646 patients treated at Roswell Park Comprehensive Cancer Center) between June 2016 and June 2017. Physician treatment recommendations made within 120 days post-test were gathered from tested patients' medical records and classified as targeted therapy, precision medicine clinical trial, immunotherapy, hormonal therapy, chemotherapy/radiation, surgery, transplant, or non-therapeutic (hospice, surveillance, or palliative care). Agreement between NGS test report targeted therapy recommendations based on the FDA variant classification and physician targeted therapy treatment recommendations were evaluated. RESULTS: Excluding variants contraindicating targeted therapy (i.e., KRAS or NRAS mutations), at least one variant with FDA level 1 companion diagnostic supporting evidence as the most actionable was identified in 14% of tests, with physicians most frequently recommending targeted therapy (48%) for patients with these results. This stands in contrast to physicians recommending targeted therapy based on test results with FDA level 2 (practice guideline) or FDA level 3 (clinical trial or off label) evidence as the most actionable result (11 and 4%, respectively). CONCLUSIONS: We found an appropriate "dose-response" relationship between the strength of clinical evidence supporting biomarker-directed targeted therapy based on application of FDA guidance for NGS test variant classification, and subsequent treatment recommendations made by treating physicians. In view of recent changes at FDA, it is paramount to define regulatory grounds and medical policy coverage for NGS testing based on this guidance.
Subject(s)
Antineoplastic Agents/therapeutic use , High-Throughput Nucleotide Sequencing/standards , Neoplasms/drug therapy , Neoplasms/genetics , Pharmacogenomic Testing/standards , Precision Medicine/standards , United States Food and Drug Administration/standards , Genetic Profile , Humans , Retrospective Studies , United StatesABSTRACT
BACKGROUND: Mediastinoscopy is considered the gold standard for preresectional staging of lung cancer. We sought to examine the effect of concomitant mediastinoscopy on postoperative pneumonia (POP) in patients undergoing lobectomy. METHODS: All patients in our institutional database (2008-2015) undergoing lobectomy who did not receive neoadjuvant therapy were included in our study. The relationship between mediastinoscopy and POP was examined using univariate (Chi square) and multivariate analyses (binary logistic regression). In order to validate our institutional findings, lobectomy data in the National Surgical Quality Improvement Program (NSQIP) from 2005 to 2014 were analyzed for these associations. RESULTS: Of 810 patients who underwent a lobectomy at our institution, 741 (91.5%) surgeries were performed by video-assisted thoracic surgery (VATS) and 487 (60.1%) patients underwent concomitant mediastinoscopy. Univariate analysis demonstrated an association between mediastinoscopy and POP in patients undergoing VATS [odds ratio (OR) 1.80; p = 0.003], but not open lobectomy. Multivariate analysis retained mediastinoscopy as a variable, although the relationship showed only a trend (OR 1.64; p = 0.1). In the NSQIP cohort (N = 12,562), concomitant mediastinoscopy was performed in 9.0% of patients, with 44.5% of all the lobectomies performed by VATS. Mediastinoscopy was associated with POP in patients having both open (OR1.69; p < 0.001) and VATS lobectomy (OR 1.72; p = 0.002). This effect remained in multivariate analysis in both the open and VATS lobectomy groups (OR 1.46, p = 0.003; and 1.53, p = 0.02, respectively). CONCLUSIONS: Mediastinoscopy may be associated with an increased risk of POP after pulmonary lobectomy. This observation should be examined in other datasets as it potentially impacts preresectional staging algorithms for patients with lung cancer.
Subject(s)
Mediastinoscopy/adverse effects , Pneumonectomy/adverse effects , Pneumonia/etiology , Postoperative Complications/etiology , Thoracic Surgery, Video-Assisted/adverse effects , Aged , Female , Humans , Male , Middle Aged , Pneumonectomy/methods , Retrospective Studies , Risk Factors , Time FactorsABSTRACT
BACKGROUND: To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D). METHODS: Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway. RESULTS: Ten patients were evaluable in the 4 weeks on/2 weeks off schedule (terminated following limited tolerability) and 47 in the 3 days on/4 days off schedule dose-escalation cohorts. On the 3 days on/4 days off schedule, RP2D was 5 mg twice daily in solid tumours (n=40); undetermined in lymphoid malignancies (n=7). Common roniciclib-related adverse events included nausea (76.6%), fatigue (65.8%), diarrhoea (63.1%), and vomiting (57.7%). Roniciclib demonstrated rapid absorption and dose-proportional increase in exposure. One partial response (1.0%) was observed. In RP2D expansion cohorts, the disease control rate (DCR) was 40.9% for patients with ovarian cancer (n=25), 17.4% for patients with SCLC (n=33), and 33.3% for patients with CDK-related tumour mutations (n=6). CONCLUSIONS: Roniciclib demonstrated an acceptable safety profile and moderate DCR in 3 days on/4 days off schedule.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Neoplasms/drug therapy , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Signal Transduction/genetics , Sulfoxides/administration & dosage , Sulfoxides/adverse effects , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/pharmacokinetics , Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclin-Dependent Kinases/genetics , Cyclin-Dependent Kinases/pharmacokinetics , Diarrhea/chemically induced , Fatigue/chemically induced , Female , Gene Expression/drug effects , Humans , Lung Neoplasms/drug therapy , Lymphoma/drug therapy , Male , Maximum Tolerated Dose , Middle Aged , Nausea/chemically induced , Neoplasms/genetics , Ovarian Neoplasms/drug therapy , Proliferating Cell Nuclear Antigen/genetics , Small Cell Lung Carcinoma/drug therapy , Vomiting/chemically inducedABSTRACT
Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1. Results Fifty-one patients received TAK-733 0.2-22 mg. Primary diagnoses included uveal melanoma (24 %), colon cancer (22 %), and cutaneous melanoma (10 %). Four patients had dose-limiting toxicities of dermatitis acneiform, plus fatigue and pustular rash in one patient, and stomatitis in one patient. The maximum tolerated dose was 16 mg. Common drug-related AEs included dermatitis acneiform (51 %), diarrhea (29 %), and increased blood creatine phosphokinase (20 %); grade ≥ 3 AEs were reported in 27 (53 %) patients. Median Tmax was 3 h; systemic exposure increased less than dose-proportionally over the dose range 0.2-22 mg. On day 21 maximum inhibition of ERK phosphorylation in peripheral blood mononuclear cells of 46-97 % was seen in patients receiving TAK-733 ≥ 8.4 mg. Among 41 response-evaluable patients, 2 (5 %) patients with cutaneous melanoma (one with BRAF L597R mutant melanoma) had partial responses. Conclusions TAK-733 had a generally manageable toxicity profile up to the maximum tolerated dose, and showed the anticipated pharmacodynamic effect of sustained inhibition of ERK phosphorylation. Limited antitumor activity was demonstrated. Further investigation is not currently planned.
Subject(s)
Antineoplastic Agents , Colonic Neoplasms/drug therapy , Melanoma/drug therapy , Protein Kinase Inhibitors , Pyridones , Pyrimidinones , Skin Neoplasms/drug therapy , Uveal Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Colonic Neoplasms/metabolism , Extracellular Signal-Regulated MAP Kinases/blood , Female , Humans , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/antagonists & inhibitors , Male , Maximum Tolerated Dose , Melanoma/metabolism , Middle Aged , Phosphorylation/drug effects , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyridones/adverse effects , Pyridones/pharmacokinetics , Pyridones/pharmacology , Pyridones/therapeutic use , Pyrimidinones/adverse effects , Pyrimidinones/pharmacokinetics , Pyrimidinones/pharmacology , Pyrimidinones/therapeutic use , Skin Neoplasms/metabolism , Treatment Outcome , Uveal Neoplasms/metabolism , Young AdultABSTRACT
BACKGROUND: Focal adhesion kinase (FAK) is overexpressed in many types of tumours, including lung cancer. Y15, a small molecule which inhibits Y397 FAK autophosphorylation, decreases growth of human neuroblastoma, breast and pancreatic cancers. In this study, we investigated the in vitro and in vivo effects of Y15, and the underlying mechanism on non-small cell lung cancer cells. METHODS: The cytotoxic effects of Y15 targeting FAK signalling were evaluated. Gene-knockdown experiments were performed to determine the anti-cancer mechanism. Xenografts with RAS or EGFR mutations were selected for in vivo Y15 treatment. RESULTS: Y15 blocked autophosphorylation of FAK in a time- and dose-dependent manner. It caused dose-dependent decrease of lung cancer cell viability and clonogenicity. Y15 inhibited tumour growth of RAS-mutant (A549 with KRAS mutation and H1299 with NRAS mutation), as well as epidermal growth factor receptor (EGFR) mutant (H1650 and H1975) lung cancer xenografts. JNK activation is a mechanism underlying Y15-induced Bcl-2 and Mcl-1 downregulation. Moreover, knockdown of Bcl-2 or Bcl-xL potentiated the effects of Y15. The combination of various inhibitors of the Bcl-2 family of proteins with FAK inhibitors demonstrated synergy in multiple lung cancer cell lines in vitro. CONCLUSIONS: FAK inhibition demonstrated efficacy both in vitro and in vivo in lung cancers with either oncogenic RAS or EGFR mutations. In addition, FAK inhibition in combination with inhibitors of Bcl-2 family of anti-apoptotic proteins has synergistic activity in these MAPK-activated non-small cell lung cancer cell line models.
Subject(s)
Carcinoma, Non-Small-Cell Lung/enzymology , Focal Adhesion Protein-Tyrosine Kinases/antagonists & inhibitors , Lung Neoplasms/enzymology , MAP Kinase Signaling System , Protein Kinase Inhibitors/pharmacology , Animals , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Dose-Response Relationship, Drug , Female , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Heterografts , Humans , Lung Neoplasms/pathology , Mice, SCID , PhosphorylationABSTRACT
BACKGROUND: Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. METHODS: We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. FINDINGS: Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7-22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2-4·8), and median duration of response was not reached (95% CI 8·31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7-10·9). 20 (17%) of 117 patients reported grade 3-4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. INTERPRETATION: Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. FUNDING: Bristol-Myers Squibb.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Comorbidity , Disease Progression , Disease-Free Survival , Drug Administration Schedule , Europe , Female , Humans , Infusions, Intravenous , Kaplan-Meier Estimate , Lung Neoplasms/metabolism , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Molecular Targeted Therapy , Nivolumab , Programmed Cell Death 1 Receptor/metabolism , Risk Factors , Signal Transduction/drug effects , Time Factors , Treatment Outcome , United StatesABSTRACT
Background This Phase 1b study aimed to determine the recommended Phase 2 dose of LY2334737, an oral pro-drug of gemcitabine, in combination with capecitabine, an oral pro-drug of 5-fluorouracil, in patients with advanced solid tumors. In addition, pharmacokinetics (PK) and tumor response were evaluated. Patients and methods Patients with advanced/metastatic solid tumors received 650 mg/m(2) capecitabine twice daily (BID) and escalating doses of LY2334737 once daily (QD; initial dose 10 mg/day), both for 14 days followed by 7-day drug holiday. Cycles were repeated until progressive disease (PD) or unacceptable toxicity. Results Fifteen patients received a median of 2 (range 1-7) treatment cycles; 14 patients discontinued due to PD, 1 due to toxicity (pyrexia). LY2334737 doses up to 40 mg/day were explored. Three dose-limiting toxicities were reported by 2 patients (fatigue, diarrhea, hyponatremia; all Grade 3). Seven patients achieved stable disease. Enrollment was stopped after unexpected hepatic toxicities were observed with LY2334737 QD in a study of Japanese patients. PK parameters for LY2334737 were consistent with the first-in-human study of LY2334737; PK data after 14 day combination treatment revealed no drug-drug interactions between LY2334737 and capecitabine. Conclusions No drug interactions or unexpected toxicities were observed in US patients when LY2334737 at doses up to 40 mg/day was administered QD in combination with capecitabine BID; the maximum tolerated dose was not reached.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Deoxyuridine/analogs & derivatives , Neoplasms/drug therapy , Prodrugs/pharmacokinetics , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols , Capecitabine/therapeutic use , Deoxyuridine/administration & dosage , Deoxyuridine/adverse effects , Deoxyuridine/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Interactions , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Prodrugs/administration & dosage , Prodrugs/adverse effectsABSTRACT
Based on preclinical data demonstrating cytotoxic synergy between sorafenib and entinostat, a phase I study of this combination was conducted in patients with advanced solid tumors. Enrollment followed the traditional "3 + 3" dose escalation scheme. Entinostat was given orally once every 2 weeks, starting at a dose of 4 mg and escalating to 6 and 10 mg every 2 weeks. Sorafenib was administered as a continuous oral dose, escalating from 200 to 400 mg twice daily. A treatment cycle was 28 days. A total of 31 patients with advanced solid tumors were enrolled on the study. The three dose-limiting toxicities (DLTs) observed were grade 3 hand-foot syndrome, nausea/vomiting, and fatigue. MTD was not reached. The recommended phase II dose was defined as the full dose of the respective drugs administered individually. The most common grade 3-4 toxicities were muscle weakness (13 %), skin rash (10 %), fatigue (6 %), diarrhea (6 %), and hand-foot syndrome (3 %). One NSCLC patient achieved a partial response. Two patients (adenocarcinoma of GE junction and Hurthle cell carcinoma of the thyroid) were on the study for more than 9 months with stable disease. The combination of entinostat and sorafenib was well tolerated. Entinostat 10 mg orally once every 2 weeks in combination with sorafenib 400 mg orally twice daily, representing full single agent doses of each drug was identified as the recommended phase 2 dose (RP2D). These data support future clinical development of the combination of entinostat and sorafenib.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Benzamides/administration & dosage , Benzamides/adverse effects , Benzamides/pharmacology , Cell Line, Tumor , Female , Histone Deacetylase Inhibitors/administration & dosage , Histone Deacetylase Inhibitors/adverse effects , Histone Deacetylase Inhibitors/pharmacology , Humans , Male , Middle Aged , Niacinamide/administration & dosage , Niacinamide/adverse effects , Niacinamide/analogs & derivatives , Niacinamide/pharmacology , Phenylurea Compounds/administration & dosage , Phenylurea Compounds/adverse effects , Phenylurea Compounds/pharmacology , Pyridines/administration & dosage , Pyridines/adverse effects , Pyridines/pharmacology , Sorafenib , Treatment OutcomeABSTRACT
PURPOSE: This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of tivantinib combined with sorafenib in patients with advanced solid tumors. MATERIALS AND METHODS: A standard 3 + 3 dose escalation design was used. At the RP2D, expansion cohorts in 5 tumor types could be enrolled. Pharmacogenetic and pharmacodynamic analysis were performed. RESULTS: Eighty-seven patients received the study treatment. The combination had no unexpected toxicities. The most common treatment-related adverse events (AE) were rash (40 %), diarrhea (38 %), and anorexia (33 %). The RP2D was tivantinib 360 mg BID and sorafenib 400 mg BID for all cancer histologies, except in hepatocellular carcinoma (HCC) patients tivantinib was 240 mg BID plus sorafenib 400 mg BID. The overall response rate was 12 % in all patients, 26 % in melanoma, 15 % in renal cell carcinoma (RCC), 10 % in HCC, and 0 % in other patients. Disease control rate (CR, PR and SD ≥8 weeks) was 58 % in all patients, 90 % in RCC, 65 % in HCC, 63 % in melanoma, 40 % in breast cancer, and 8 % in NSCLC patients. CONCLUSIONS: The combination treatment could be administered at full standard single-agent doses in all patients except those with HCC, where tivantinib was lowered to 240 mg BID. Preliminary evidence of anticancer activity was observed in patients with RCC, HCC, and melanoma, including patients refractory to sorafenib and/or other anti-VEGF pathway therapies. The combination treatment has therapeutic potential in treating a variety of solid tumors.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cytochrome P-450 CYP2C19/genetics , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/genetics , Neoplasms/metabolism , Niacinamide/administration & dosage , Niacinamide/adverse effects , Niacinamide/analogs & derivatives , Niacinamide/pharmacokinetics , Niacinamide/pharmacology , Phenylurea Compounds/administration & dosage , Phenylurea Compounds/adverse effects , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/pharmacology , Polymorphism, Genetic , Proto-Oncogene Proteins c-met/metabolism , Pyrrolidinones/administration & dosage , Pyrrolidinones/adverse effects , Pyrrolidinones/pharmacokinetics , Pyrrolidinones/pharmacology , Quinolines/administration & dosage , Quinolines/adverse effects , Quinolines/pharmacokinetics , Quinolines/pharmacology , Sorafenib , Treatment Outcome , Young AdultABSTRACT
PURPOSE: Complementary and alternative medicine (CAM) use has been increasing among cancer patients. This study characterizes the use of CAM among patients with thoracic malignancies. METHODS: This cross sectional study was conducted at a National Cancer Institute-designated comprehensive cancer center among adult patients diagnosed with thoracic malignancies. The primary outcome was a self-reported use of CAM, defined as the use of any type of CAM beyond routine vitamin/mineral supplementation alone. A logistic regression model was developed to explore predictors of CAM use. RESULTS: A total of 108 patients completed a standardized survey (59% response rate). Overall, 42% of respondents reported the use of at least one type of CAM. Users and non-users of CAM did not differ based upon demographics, diagnosis, staging, smoking status, quality of life, or perceived understanding of cancer diagnosis. In the multivariate analysis, patients who reported feeling fearful about their future were four times more likely to be CAM users when compared to those who did not specify this emotion (odds ratio=4.18; 95% CI=1.23-14.12; p=0.02). Commonly cited reasons for CAM use were to support one's self, boost immunity, and for improvements in emotional and/or spiritual well-being. CONCLUSIONS: Prevalence of CAM use among cancer patients in this study was similar to the general US population. Feeling fearful about the future was associated with CAM use. Results suggest that patients may be turning to CAM as a therapeutic adjunct to actively cope with emotional distress surrounding the cancer experience.
Subject(s)
Complementary Therapies/statistics & numerical data , Thoracic Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Complementary Therapies/psychology , Cross-Sectional Studies , Data Collection , Female , Humans , Logistic Models , Male , Middle Aged , Motivation , Multivariate Analysis , Odds Ratio , Self Report , Thoracic Neoplasms/psychology , United StatesABSTRACT
Introduction: EML4-ALK is an oncogenic driver, seen in around five per cent of advanced non-small-cell lung cancer (NSCLC) patients, which can be targeted with anaplastic lymphoma kinase tyrosine kinase inhibitors with great response rates. Disease flare refers to sudden rapid disease worsening on tyrosine kinase inhibitors (TKI) discontinuation, which is associated with shorter survival and worse outcomes. Here, we review cases previously published in the literature where patients developed disease flares, and contrast this with our patients who had prolonged survival despite TKI discontinuation. Case description: We report three different patients with advanced ALK-positive NSCLC seen at our institute, who had EML4-ALK translocation variant 1 oncogenic driver on next-generation sequencing. They received treatment with several different ALK inhibitors before opting to discontinue TKI. They were able to come off TKI safely without developing disease flare and had prolonged survival. Discussion: Shorter time to progression on TKI, presence of symptoms with disease progression or central nervous system/pleural metastasis have been previously linked with development of flare, although this was not seen in our case series. Tumour response at the time of treatment discontinuation, line of therapy, overall disease burden, fusion variant and co-alteration status can affect the prognosis of these patients after ALK TKI cessation. In particular, variant 1 and wild-type TP53 status may be a suitable patient population for dose optimisation strategies. Intermittent TKI dosing strategies may help to avoid acquiring resistance mutations and prevent long-term treatment toxicities. Conclusion: It is important for clinicians to identify patients at risk for developing disease flare on TKI discontinuation to improve outcomes. Intermittent TKI dosing strategies require further investigation. LEARNING POINTS: Patients who develop disease flare after cessation have poor survival and worse outcomes.Certain phenotypic and molecular characteristics of the tumour may help clinicians identify which patients are likely and which are unlikely to develop disease flare on TKI discontinuation.Advanced ALK-positive NSCLC with variant 1 and wild-type TP53 may be a suitable patient population for intermittent TKI dosing investigations.
ABSTRACT
Pembrolizumab, a widely used immune checkpoint inhibitor (ICI), has revolutionized the treatment of non-small cell lung cancer (NSCLC). Identifying unique tumor characteristics in patients likely to respond to pembrolizumab could help the clinical adjudication and development of a personalized therapeutic strategy. In this retrospective study, we reviewed the clinical data and pathological features of 84 NSCLC patients treated with pembrolizumab. We examined the correlation between the clinical and demographic characteristics and the tumor histopathologic features obtained before immunotherapy. The response to pembrolizumab therapy was evaluated via the Response Evaluation Criteria in Solid Tumors (RECIST). The clinical data and cancer tissue characteristics were assessed and compared among three groups according to the following RECIST: the responsive group (RG), the stable disease group (SD), and the progressive disease group (PD), where the RG comprised patients with either a complete response (CR) or a partial response (PR). The overall survival rate of the RG group was significantly higher than the SD and PD groups. In addition, the percentage of pre-treatment viable tumor cell content in the RG and SD groups was significantly higher. At the same time, the extracellular stroma proportion was significantly lower than that of the PD group. The number of tumor-infiltrating lymphocytes (TILs) in the RG group was significantly higher than in the PD group. There were no significant differences in tumor necrosis, the stroma composition, PD-L1 expression level (TPS 1-49% vs. ≥50%), and treatment response. In conclusion, our population of NSCLC patients who experienced positive treatment responses to pembrolizumab therapy had a better prognosis compared to patients with either SD or PD. Moreover, the relative proportions of viable tumor cells to tumor-associated lymphocytes were associated with responsiveness to treatment. It is expected that larger prospective clinical studies will further validate these findings.