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INTRODUCTION: Squamous cell cancer (SqCC) is a lung cancer subtype with few targeted therapy options. Molecular characterization, that is, by next-generation sequencing (NGS), is needed to identify potential targets. Lung Cancer Master Protocol Southwest Oncology Group S1400 enrolled patients with previously treated stage IV or recurrent SqCC to assess NGS biomarkers for therapeutic sub-studies. METHODS: Tumors underwent NGS using Foundation Medicine's FoundationOne research platform, which sequenced the exons and/or introns of 313 cancer-related genes. Mutually exclusive gene set analysis and Selected Events Linked by Evolutionary Conditions across Human Tumors were performed to identify mutually exclusive and co-occurring gene alterations. Comparisons were performed with data on 495 lung SqCC downloaded from The Cancer Genome Atlas. Cox proportional hazards models were used to assess associations between genetic variants and survival. RESULTS: NGS data are reported for 1672 patients enrolled on S1400 between 2014 and 2019. Mutually exclusive gene set analysis identified two non-overlapping sets of mutually exclusive alterations with a false discovery rate of less than 15%: NFE2L2, KEAP1, and PARP4; and CDKN2A and RB1. PARP4, a relatively uncharacterized gene, showed three frequent mutations suggesting functional significance: 3116T>C (I1039T), 3176A>G (Q1059R), and 3509C>T (T1170I). When taken together, NFE2L2 and KEAP1 alterations were associated with poorer survival. CONCLUSIONS: As the largest dataset to date of lung SqCC profiled on a clinical trial, the S1400 NGS dataset establishes a rich resource for biomarker discovery. Mutual exclusivity of PARP4 and NFE2L2 or KEAP1 alterations suggests that PARP4 may have an uncharacterized role in a key pathway known to impact oxidative stress response and treatment resistance.
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Neurofibromatosis type 1, a genetic disorder caused by pathogenic germline variations in NF1, predisposes individuals to the development of tumors, including cutaneous and plexiform neurofibromas (CNs and PNs), optic gliomas, astrocytomas, juvenile myelomonocytic leukemia, high-grade gliomas and malignant peripheral nerve sheath tumors (MPNSTs), which are chemotherapy- and radiation-resistant sarcomas with poor survival. Loss of NF1 also occurs in sporadic tumors, such as glioblastoma (GBM), melanoma, breast, ovarian and lung cancers. We performed a high-throughput screen for compounds that were synthetic lethal with NF1 loss, which identified several leads, including the small molecule Y102. Treatment of cells with Y102 perturbed autophagy, mitophagy and lysosome positioning in NF1-deficient cells. A dual proteomics approach identified BLOC-one-related complex (BORC), which is required for lysosome positioning and trafficking, as a potential target of Y102. Knockdown of a BORC subunit using siRNA recapitulated the phenotypes observed with Y102 treatment. Our findings demonstrate that BORC might be a promising therapeutic target for NF1-deficient tumors.
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Lisosomas , Neurofibromina 1 , Humanos , Lisosomas/metabolismo , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Neurofibromatosis 1/metabolismo , Neurofibromatosis 1/genética , Neurofibromatosis 1/patología , Autofagia/efectos de los fármacos , Mutaciones Letales Sintéticas , Transporte de Proteínas/efectos de los fármacosRESUMEN
In this secondary analysis of specimens from the CANTOS trial, the investigators find that patients with clonal hematopoiesis mutations, particularly in the TET2 gene, predict a benefit of decreased cancer risk with the administration of the anti-IL1ß agent canakinumab. Despite small numbers and the need for prospective validation, the findings are exciting as they demonstrate the potential for personalized chemoprevention approaches. Such personalized approaches can potentially enhance the feasibility of cancer prevention trials. See related article by Woo et al., p. XX (2).
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Clinical trials are essential for advancing oncology treatment strategies and have contributed significantly to the decline in cancer mortality rates over the past decades. Traditional explanatory trials, focused on establishing intervention efficacy in ideal settings, often lack generalizability and may not reflect real-world patient care scenarios. Furthermore, increasing complexity in cancer clinical trial design has led to challenges such as protocol deviations, slow enrollment leading to lengthened durations of trial, and escalating costs. By contrast, pragmatic trials aim to assess intervention effectiveness in more representative patient populations under routine clinical conditions. Here, we review the principles, methodologies, challenges, and advantages of incorporating pragmatic features (PFs) into cancer clinical trials. We illustrate the application of pragmatic trial designs in oncology and discuss the QUASAR collaborative, TAPUR study, and the ongoing PRAGMATICA-LUNG trial. Although not all oncology trials may be amenable to adopting fully pragmatic designs, integration of PFs when feasible will enhance trial generalizability and real-world applicability. Project Pragmatica and similar initiatives advocate for the integration of real-world practice with clinical trials, fostering a nuanced approach to oncology research that balances efficacy and effectiveness assessments, ultimately with a goal of improving patient outcomes.
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Ensayos Clínicos como Asunto , Neoplasias , Humanos , Neoplasias/terapia , Proyectos de Investigación , Ensayos Clínicos Pragmáticos como Asunto/métodos , Oncología Médica/métodosRESUMEN
PURPOSE: Lung Cancer Master Protocol (Lung-MAP), a public-private partnership, established infrastructure for conducting a biomarker-driven master protocol in molecularly targeted therapies. We compared characteristics of patients enrolled in Lung-MAP with those of patients in advanced non-small-cell lung cancer (NSCLC) trials to examine if master protocols improve trial access. METHODS: We examined patients enrolled in Lung-MAP (2014-2020) according to sociodemographic characteristics. Proportions for characteristics were compared with those for a set of advanced NSCLC trials (2001-2020) and the US advanced NSCLC population using SEER registry data (2014-2018). Characteristics of patients enrolled in Lung-MAP treatment substudies were examined in subgroup analysis. Two-sided tests of proportions at an alpha of .01 were used for all comparisons. RESULTS: A total of 3,556 patients enrolled in Lung-MAP were compared with 2,215 patients enrolled in other NSCLC studies. Patients enrolled in Lung-MAP were more likely to be 65 years and older (57.2% v 46.3%; P < .0001), from rural areas (17.3% v 14.4%; P = .004), and from socioeconomically deprived neighborhoods (42.2% v 36.7%, P < .0001), but less likely to be female (38.6% v 47.2%; P < .0001), Asian (2.8% v 5.1%; P < .0001), or Hispanic (2.4% v 3.8%; P = .003). Among patients younger than 65 years, Lung-MAP enrolled more patients using Medicaid/no insurance (27.6% v 17.8%; P < .0001). Compared with the US advanced NSCLC population, Lung-MAP under represented patients 65 years and older (57.2% v 69.8%; P < .0001), females (38.6% v 46.0%; P < .0001), and racial or ethnic minorities (14.8% v 21.5%; P < .0001). CONCLUSION: Master protocols may improve access to trials using novel therapeutics for older patients and socioeconomically vulnerable patients compared with conventional trials, but specific patient exclusion criteria influenced demographic composition. Further research examining participation barriers for under represented racial or ethnic minorities in precision medicine clinical trials is warranted.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Estados Unidos/epidemiología , Humanos , Femenino , Masculino , Neoplasias Pulmonares/terapia , Carcinoma de Pulmón de Células no Pequeñas/terapia , Terapia Molecular Dirigida , Pacientes , PulmónRESUMEN
Therapeutic targeting of RAS-mutated cancers is difficult, whereas prevention or interception (treatment before or in the presence of preinvasive lesions) preclinically has proven easier. In the A/J mouse lung model, where different carcinogens induce tumors with different KRAS mutations, glucocorticoids and retinoid X receptor (RXR) agonists are effective agents in prevention and interception studies, irrespective of specific KRAS mutations. In rat azoxymethane-induced colon tumors (45% KRAS mutations), cyclooxygenase 1/2 inhibitors and difluoromethylornithine are effective in preventing or intercepting KRAS-mutated or wild-type tumors. In two KRAS-mutant pancreatic models multiple COX 1/2 inhibitors are effective. Furthermore, combining a COX and an EGFR inhibitor prevented the development of virtually all pancreatic tumors in transgenic mice. In the N-nitroso-N-methylurea-induced estrogen receptor-positive rat breast model (50% HRAS mutations) various selective estrogen receptor modulators, aromatase inhibitors, EGFR inhibitors, and RXR agonists are profoundly effective in prevention and interception of tumors with wild-type or mutant HRAS, while the farnesyltransferase inhibitor tipifarnib preferentially inhibits HRAS-mutant breast tumors. Thus, many agents not known to specifically inhibit the RAS pathway, are effective in an organ specific manner in preventing or intercepting RAS-mutated tumors. Finally, we discuss an alternative prevention and interception approach, employing vaccines to target KRAS.
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Neoplasias Pancreáticas , Vacunas , Ratones , Ratas , Animales , Proteínas Proto-Oncogénicas p21(ras)/genética , Ratones Transgénicos , Mutación , Receptores ErbB , Prevención PrimariaRESUMEN
The neoadjuvant use of immune checkpoint inhibitors (ICI) in resectable non-small cell lung cancer (NSCLC) is being increasingly adopted, but questions about the most appropriate applications remain. Although patients with resectable NSCLC are often treated with surgery and adjuvant chemotherapy or targeted therapies +/- radiotherapy, they still have a high risk of recurrence and death. In recent years, immune checkpoint inhibitors (ICI) (anti-PD-1/PD-L1 and anti-CTLA-4) have provided a new and effective therapeutic strategy for the treatment of advanced NSCLC. Therefore, it is possible that ICIs for early-stage NSCLC may follow the pattern established in metastatic disease. Currently, there are several ongoing trials to determine the efficacy in the neoadjuvant setting for patients with local or regional disease. To date, only nivolumab in combination with chemotherapy has been approved by the U.S. FDA in the preoperative setting, but data continue to evolve rapidly, and treatment guidelines need to be determined. In this article, we review the current preclinical and clinical evidence on neoadjuvant ICIs alone and combination in the treatment of early-stage NSCLC.
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PURPOSE: Efficacy of MEK inhibitors in KRAS+ NSCLC may differ based on specific KRAS mutations and comutations. Our hypothesis was that docetaxel and trametinib would improve activity in KRAS+ NSCLC and specifically in KRAS G12C NSCLC. PATIENTS AND METHODS: S1507 is a single-arm phase II study assessing the response rate (RR) with docetaxel plus trametinib in recurrent KRAS+ NSCLC and secondarily in the G12C subset. The accrual goal was 45 eligible patients, with at least 25 with G12C mutation. The design was two-stage design to rule out a 17% RR, within the overall population at the one-sided 3% level and within the G12C subset at the 5% level. RESULTS: Between July 18, 2016, and March 15, 2018, 60 patients were enrolled with 53 eligible and 18 eligible in the G12C cohort. The RR was 34% [95% confidence interval (CI), 22-48] overall and 28% (95% CI, 10-53) in G12C. Median PFS and OS were 4.1 and 3.3 months and 10.9 and 8.8 months, overall and in the subset, respectively. Common toxicities were fatigue, diarrhea, nausea, rash, anemia, mucositis, and neutropenia. Among 26 patients with known status for TP53 (10+ve) and STK11 (5+ve), OS (HR, 2.85; 95% CI, 1.16-7.01), and RR (0% vs. 56%, P = 0.004) were worse in patients with TP53 mutated versus wild-type cancers. CONCLUSIONS: RRs were significantly improved in the overall population. Contrary to preclinical studies, the combination showed no improvement in efficacy in G12C patients. Comutations may influence therapeutic efficacy of KRAS directed therapies and are worthy of further evaluation. See related commentary by Cantor and Aggarwal, p. 3563.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Docetaxel/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , MutaciónRESUMEN
There are major hurdles to the use of tyrosine kinase inhibitors (TKIs) and any other agents with significant toxicities (which means practically the preponderance of potential effective agents) in the context of prevention/anti-progression (interception) studies. We will discuss epidermal growth factor receptor (EGFR) inhibitors as examples, both in a primary prevention setting, where agent(s) are administered to individuals with no cancer but who might be considered at higher risk due to a variety of factors, and in anti-progression/interception studies, where agent(s) are administered to persons with known preinvasive lesions (e.g., colon adenomas, lung nodules, ductal carcinoma in situ (DCIS), or pancreatic intraepithelial neoplasia (PanIN) lesions in the pancreas) in an attempt to reverse or inhibit progression of these lesions. Multiple potential hurdles will be examined, including: a) toxicity of agents, b) the likely range of subtypes of cancers affected by a given treatment (e.g., EGFR inhibitors against EGFR mutant lung adenocarcinomas), c) the availability of practical endpoints besides the blocking of cancer formation or pharmacokinetics related to the agents administered in a primary prevention study, and d) the interpretation of the regression or blockage of new preinvasive lesions in the anti-progression study. Such an anti-progression approach may help address some of the factors commented on regarding primary prevention (toxicity, potential target organ cancer subtypes) but still leaves major questions regarding interpretation of modulation of preinvasive endpoints when it may not be clear how frequently they progress to clinical cancer. Additionally, we address whether certain recent preclinical findings might be able to reduce the toxicities associated with these agents and perhaps even increase their potential efficacy. Antibodies and TKIs other than the EGFR inhibitors are not discussed because few if any had been tested as monotherapies in humans, making their efficacy harder to predict, and because a number have relatively rare but quite striking toxicities. Furthermore, most of the practical hurdles raised regarding the EGFR inhibitors are relevant to the other TKIs. Finally, we briefly discuss whether early detection employing blood or serum samples may allow identification of high-risk groups more amenable to agents with greater toxicity.
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BACKGROUND: Immunotherapy combinations including ipilimumab and nivolumab are now the standard of care for untreated metastatic renal cell carcinoma (mRCC). Biomarkers of response are lacking to predict patients who will have a favorable or unfavorable response to immunotherapy. This study aimed to use the OmniSeq transcriptome-based platform to develop biomarkers of response to immunotherapy. METHODS: Two cohorts of patients were retrospectively collected. These included an investigational cohort of patients with mRCC treated with immune checkpoint inhibitor therapy from five institutions, and a subsequent validation cohort of patients with mRCC treated with combination ipilimumab and nivolumab from two institutions (Duke Cancer Institute and Cleveland Clinic Taussig Cancer Center). Tissue-based RNA sequencing was performed using the OmniSeq Immune Report Card on banked specimens to identify gene signatures and immune checkpoints associated with differential clinical outcomes. A 5-gene expression panel was developed based on the investigational cohort and was subsequently evaluated in the validation cohort. Clinical outcomes including progression-free survival (PFS) and overall survival (OS) were extracted by retrospective chart review. Objective response rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1. RESULTS: The initial investigation cohort identified 86 patients with mRCC who received nivolumab (80%, 69/86), ipilimumab/nivolumab (14%, 12/86), or pembrolizumab (6%, 5/86). A gene expression score was created using the top five genes found in responders versus non-responders (FOXP3, CCR4, KLRK1, ITK, TIGIT). The ORR in patients with high gene expression (GEhigh) on the 5-gene panel was 29% (14/48), compared with low gene expression (GElow) 3% (1/38, χ2 p=0.001). The validation cohort was comprised of 62 patients who received ipilimumab/nivolumab. There was no difference between GEhigh and GElow in terms of ORR (44% vs 38.5%), PFS (HR 1.5, 95% CI 0.58 to 3.89), or OS (HR 0.96, 95% CI 0.51 to 1.83). Similarly, no differences in ORR, PFS or OS were observed when patients were stratified by tumor mutational burden (high=top 20%), PD-L1 (programmed death-ligand 1) expression by immunohistochemistry or RNA expression, or CTLA-4 (cytotoxic T-lymphocytes-associated protein 4) RNA expression. The International Metastatic RCC Database Consortium (IMDC) risk score was prognostic for OS but not PFS. CONCLUSION: A 5-gene panel that was associated with improved ORR in a predominantly nivolumab monotherapy population of patients with mRCC was not predictive for radiographic response, PFS, or OS among patients with mRCC treated with ipilimumab and nivolumab.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Antígeno B7-H1/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Antígeno CTLA-4/uso terapéutico , Factores de Transcripción Forkhead , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ipilimumab/farmacología , Ipilimumab/uso terapéutico , Neoplasias Renales/patología , Nivolumab/farmacología , Nivolumab/uso terapéutico , Estudios Retrospectivos , Microambiente TumoralRESUMEN
BACKGROUND: Despite progress in developing learning health systems (LHS) and associated metrics of success, a gap remains in identifying measures to guide the implementation and assessment of the impact of an oncology LHS. Our aim was to identify a balanced set of measures to guide a person-centered oncology LHS. METHODS: A modified Delphi process and clinical value compass framework were used to prioritize measures for tracking LHS performance. A multidisciplinary group of 77 stakeholders, including people with cancer and family members, participated in 3 rounds of online voting followed by 50-minute discussions. Participants rated metrics on perceived importance to the LHS and discussed priorities. RESULTS: Voting was completed by 94% of participants and prioritized 22 measures within 8 domains. Patient and caregiver factors included clinical health (Eastern Cooperative Oncology Group Performance Status, survival by cancer type and stage), functional health and quality of life (Patient Reported Outcomes Measurement Information System [PROMIS] Global-10, Distress Thermometer, Modified Caregiver Strain Index), experience of care (advance care planning, collaboRATE, PROMIS Self-Efficacy Scale, access to care, experience of care, end-of-life quality measures), and cost and resource use (avoidance and delay in accessing care and medications, financial hardship, total cost of care). Contextual factors included team well-being (Well-being Index; voluntary staff turnover); learning culture (Improvement Readiness, compliance with Commission on Cancer quality of care measures); scholarly engagement and productivity (institutional commitment and support for research, academic productivity index); and diversity, equity, inclusion, and belonging (screening and follow-up for social determinants of health, inclusivity of staff and patients). CONCLUSIONS: The person-centered LHS value compass provides a balanced set of measures that oncology practices can use to monitor and evaluate improvement across multiple domains.
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Aprendizaje del Sistema de Salud , Neoplasias , Cuidadores , Humanos , Oncología Médica , Neoplasias/terapia , Calidad de VidaRESUMEN
PURPOSE: Resistance to immune checkpoint inhibition (ICI) in advanced non-small-cell lung cancer (NSCLC) represents a major unmet need. Combining ICI with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types. METHODS: In this randomized phase II Lung-MAP nonmatch substudy (S1800A), patients ineligible for a biomarker-matched substudy with NSCLC previously treated with ICI and platinum-based chemotherapy and progressive disease at least 84 days after initiation of ICI were randomly assigned to receive ramucirumab plus pembrolizumab (RP) or investigator's choice standard of care (SOC: docetaxel/ramucirumab, docetaxel, gemcitabine, and pemetrexed). With a goal of 130 eligible patients, the primary objective was to compare overall survival (OS) using a one-sided 10% level using the better of a standard log-rank (SLR) and weighted log-rank (WLR; G[rho = 0, gamma = 1]) test. Secondary end points included objective response, duration of response, investigator-assessed progression-free survival, and toxicity. RESULTS: Of 166 patients enrolled, 136 were eligible (69 RP; 67 SOC). OS was significantly improved with RP (hazard ratio [80% CI]: 0.69 [0.51 to 0.92]; SLR one-sided P = .05; WLR one-sided P = .15). The median (80% CI) OS was 14.5 (13.9 to 16.1) months for RP and 11.6 (9.9 to 13.0) months for SOC. OS benefit for RP was seen in most subgroups. Investigator-assessed progression-free survival (hazard ratio [80% CI]: 0.86 [0.66 to 1.14]; one-sided SLR, P = .25 and .14 for WLR) and response rates (22% RP v 28% SOC, one-sided P = .19) were similar between arms. Grade ≥ 3 treatment-related adverse events occurred in 42% of patients in the RP group and 60% on SOC. CONCLUSION: This randomized phase II trial demonstrated significantly improved OS with RP compared with SOC in patients with advanced NSCLC previously treated with ICI and chemotherapy. The safety was consistent with known toxicities of both drugs. These data warrant further evaluation.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/patología , Docetaxel/uso terapéutico , Humanos , Inmunoterapia , Pulmón/patología , Neoplasias Pulmonares/patología , Nivel de Atención , Factor A de Crecimiento Endotelial Vascular , RamucirumabRESUMEN
INTRODUCTION: The sequence of chemotherapy and pembrolizumab may affect antitumor immune response and efficacy of immunotherapy. METHODS: This multicenter, randomized, phase 2 trial was designed to evaluate the efficacy of two sequences of chemotherapy and pembrolizumab in patients with stage 4 NSCLC. Both arms were considered investigational, and the study used a "pick a winner" design. The primary end point was objective response rate by independent radiologic review after eight cycles (24 wk). Patients were randomized 1:1 to arm A (chemotherapy for four cycles followed by pembrolizumab for four cycles) or arm B (pembrolizumab for four cycles followed by chemotherapy for four cycles). Patients in both arms without disease progression after the initial eight cycles continued pembrolizumab until disease progression, unacceptable toxicity, or a maximum of 2 years. RESULTS: From March 2016 to July 2018, a total of 90 eligible patients were randomized (43 patients to arm A and 47 patients to arm B). The objective response rate at 24 weeks in arms A and B was 39.5 % (95 % confidence interval [CI]: 24.9%-54.1 %) and 40.4 % (95 % CI: 26.4%-54.5 %), respectively (p = 0.93). The progression-free survival in arms A and B was as follows: hazard ratio of B versus A equals to 1.06, 95 % CI: 0.68-1.66, p value equals to 0.84, and median progression-free survival of 5.8 months and 4 months, respectively. The overall survival was as follows: hazard ratio of B versus A equals to 1.04, 95 % CI: 0.63-1.74, p value equals to 0.85, and median overall survival of 15.5 months and 14 months, respectively. CONCLUSIONS: Additional evaluation of either sequence in a phase 3 trial is not warranted.
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BACKGROUND: This study assessed the checkpoint kinase 1 inhibitor prexasertib in patients with extensive-stage small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: This was a parallel-cohort phase II study of 105 mg/m2 prexasertib once every 14 days for patients who progressed after no more than two prior therapies and had platinum-sensitive (Cohort 1) or platinum-resistant/platinum-refractory (Cohort 2) disease. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Exploratory endpoints included biomarker identification and assessment of an alternative regimen (Cohort 3: 40 mg/m2 days 1-3, 14-day cycle). RESULTS: In Cohort 1 (n = 58), ORR was 5.2%; DCR, 31%; median PFS, 1.41 months (95% confidence interval [CI], 1.31-1.64); and median OS, 5.42 months (95% CI, 3.75-8.51). In Cohort 2 (n = 60), ORR was 0%; DCR, 20%; median PFS, 1.36 months (95% CI, 1.25-1.45); and median OS, 3.15 months (95% CI, 2.27-5.52). The most frequent all-grade, related, treatment-emergent adverse events were decreased neutrophil count (Cohort 1, 69.6%; Cohort 2, 73.3%), decreased platelet count (Cohort 1, 51.8%; Cohort 2, 50.0%), decreased white blood cell count (Cohort 1, 28.6%; Cohort 2, 40.0%), and anemia (Cohort 1, 39.3%; Cohort 2, 28.3%). Eleven patients (19.6%) in Cohort 1 and one patient (1.7%) in Cohort 2 experienced grade ≥3 febrile neutropenia. Prexasertib pharmacokinetics were consistent with prior studies. Cohort 3 outcomes were similar to those of Cohorts 1 and 2. No actionable biomarkers were identified. CONCLUSION: Prexasertib did not demonstrate activity to warrant future development as monotherapy in ED-SCLC.
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Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/uso terapéutico , Pirazoles/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND: Chemotherapy-induced myelosuppression (CIM) and its sequalae cause significant side effects and harm to quality of life. Trilaciclib is an intravenous CDK4/6 inhibitor that is administered prior to chemotherapy to protect hematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection). PATIENTS AND METHODS: Data from three randomized, double-blind, placebo-controlled studies (NCT02499770, NCT03041311, and NCT02514447) were pooled to evaluate the effects of trilaciclib administered prior to standard-of-care chemotherapy (first-line etoposide plus carboplatin [E/P], first-line E/P plus atezolizumab, and second-/third-line topotecan) in patients with extensive-stage small cell lung cancer (ES-SCLC). The primary endpoints were duration of severe neutropenia (absolute neutrophil count < 0.5 × 109 cells/L) in cycle 1 and occurrence of severe neutropenia. Additional prespecified endpoints further assessed the effect of trilaciclib on myeloprotection, health-related quality of life (HRQoL), antitumor efficacy, and safety. RESULTS: Of 242 randomized patients, 123 received trilaciclib and 119 received placebo. Compared with placebo, administration of trilaciclib prior to chemotherapy resulted in significant decreases in most measures of multilineage CIM. The reduction in hematologic toxicity translated into the reduced need for supportive care interventions and hospitalizations due to CIM or sepsis and improvements in HRQoL domains related to the protected cell lineages, including fatigue, physical wellbeing, and functional wellbeing. Antitumor efficacy was similar for patients receiving trilaciclib or placebo. CONCLUSION: Administering trilaciclib prior to chemotherapy resulted in clinically meaningful reductions in CIM and its consequences and improved patient HRQoL, with no impact on the antitumor efficacy of three individual chemotherapy regimens used in the first- or second-/third-line treatment of ES-SCLC.
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Médula Ósea/efectos de los fármacos , Ensayos Clínicos Fase II como Asunto , Medición de Resultados Informados por el Paciente , Pirimidinas/farmacología , Pirroles/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Antineoplásicos/uso terapéutico , Método Doble Ciego , Humanos , TopotecanRESUMEN
INTRODUCTION: JUNIPER compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, with erlotinib in patients with non-small cell lung cancer (NSCLC) harboring a Kirsten rat sarcoma (KRAS) mutation. METHODS: JUNIPER was a Phase III, multicenter, randomized, open-label trial of abemaciclib versus erlotinib in patients with stage IV NSCLC and a detectable mutation in codons 12 or 13 of the KRAS oncogene, who progressed after platinum-based chemotherapy and 1 additional therapy (could include immune checkpoint inhibitor therapy). Randomized patients (3:2) received either 200 mg abemaciclib twice daily or 150 mg erlotinib once daily with best supportive care until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS); secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and safety. RESULTS: Between December 2014 and April 2017, 453 patients were randomly assigned to receive abemaciclib (N = 270) or erlotinib (N = 183). Median OS was 7.4 months (95% confidence interval [CI]: 6.5, 8.8) with abemaciclib and 7.8 months (95% CI: 6.4, 9.5) with erlotinib (hazard ratio [HR] = 0.968 [95% CI: 0.768, 1.219]; p = .77). Median PFS was 3.6 months (95% CI: 2.8, 3.8) with abemaciclib and 1.9 months (95% CI: 1.9, 2.0) with erlotinib (HR = 0.583 [95% CI: 0.470, 0.723]; p <.000001). ORR was 8.9% and 2.7% (p = .010), and the disease control rate was 54.4% and 31.7% (p <.001) with abemaciclib and erlotinib, respectively. Safety results reflected the known safety profiles of abemaciclib and erlotinib. CONCLUSIONS: In this study, the primary endpoint of OS was not met; PFS and ORR were improved with manageable toxicity in the abemaciclib arm. The increases in response rates and PFS support further investigation of abemaciclib in other NSCLC subpopulations or in combination with other agents. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier: NCT02152631.
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BACKGROUND: Combination treatment with chemotherapy and immune checkpoint inhibitors (ICIs) has demonstrated meaningful clinical benefit to patients. However, chemotherapy-induced damage to the immune system can potentially diminish the efficacy of chemotherapy/ICI combinations. Trilaciclib, a highly potent, selective and reversible cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor in development to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy, has demonstrated proof of concept in recent clinical trials. Furthermore, CDK4/6 inhibition has been shown to augment T-cell activation and antitumor immunity in preclinical settings. Therefore, addition of trilaciclib has the potential to further enhance the efficacy of chemotherapy and ICI combinations. METHODS: In murine syngeneic tumor models, a schedule of 3 weekly doses of trilaciclib was combined with chemotherapy/ICI regimens to assess the effect of transient CDK4/6 inhibition on antitumor response and intratumor T-cell proliferation and function. Peripheral T-cell status was also analyzed in patients with small cell lung cancer (SCLC) treated with chemotherapy with or without trilaciclib to gain insights into the effect of transient exposure of trilaciclib on T-cell activation. RESULTS: Preclinically, the addition of trilaciclib to chemotherapy/ICI regimens enhanced antitumor response and overall survival compared with chemotherapy and ICI combinations alone. This effect is associated with the modulation of the proliferation and composition of T-cell subsets in the tumor microenvironment and increased effector function. Transient exposure of trilaciclib in patients with SCLC during chemotherapy treatment both preserved and increased peripheral lymphocyte counts and enhanced T-cell activation, suggesting that trilaciclib not only preserved but also enhanced immune system function. CONCLUSIONS: Transient CDK4/6 inhibition by trilaciclib was sufficient to enhance and prolong the duration of the antitumor response by chemotherapy/ICI combinations, suggesting a role for the transient cell cycle arrest of tumor immune infiltrates in remodeling the tumor microenvironment. These results provide a rationale for combining trilaciclib with chemotherapy/ICI regimens to improve antitumor efficacy in patients with cancer.
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Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Activación de Linfocitos/efectos de los fármacos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Animales , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Pulmonares/patología , Ratones , Carcinoma Pulmonar de Células Pequeñas/patologíaRESUMEN
BACKGROUND: There are limited data and conflicting guideline recommendations regarding the role of neuroimaging in the pretreatment evaluation of non-small cell lung cancer (NSCLC). METHODS: We performed a retrospective, pragmatic cohort study of patients with NSCLC diagnosed between January 1 and December 31, 2015. Eligible patients were identified from an institutional tumor registry. We collected all records of pretreatment neuroimaging within 12 weeks of diagnosis, including CT head (CT) and MRI brain (MRI). We abstracted the indication for neuroimaging, presence of central neurologic symptoms and cancer stage (with and without neuroimaging findings) from the tumor registry and the electronic health record. RESULTS: We identified 216 evaluable patients with newly diagnosed NSCLC. 157 of 216 patients (72.7%) underwent neuroimaging as part of initial staging, and 41 (26%) were found to have brain metastases. Of 43 patients with central neurologic symptoms at the time of neuroimaging, 28 (67%) had brain metastasis. In patients without central neurologic symptoms, brain metastases were discovered in 0 of 33 patients with clinical stage I or II, 4 of 36 (11%) with clinical stage III and 9 of 45 (20%) with clinical stage IV disease. CONCLUSIONS: In patients with early stage NSCLC (i.e. clinical stage I and II) without central neurologic symptoms, brain metastases are unlikely. The continued use of neuroimaging in the pretreatment evaluation of clinical stage I patients without central neurologic symptoms is not needed.