RESUMEN
BACKGROUND: Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity. METHODS: In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed. RESULTS: A total of 137 patients (60 with non-small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib. CONCLUSIONS: Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.).
Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Colorrectales , Inhibidores Enzimáticos , Neoplasias Pulmonares , Humanos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Administración Oral , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/uso terapéuticoRESUMEN
Many approved drugs demonstrate different pharmacokinetics, pharmacodynamics, and/or safety across racial and ethnic groups. The primary objective of the current study was to summarize the racial and ethnic makeup of cancer clinical drug trials using cancer drugs approved by the U.S. Food and Drug Administration (FDA) between January 1, 2010, and July 31, 2016. In clinical studies used for FDA approvals, 82.3% of participants identified as white, 10.2% as Asian, 2.3% as black, and 4.7% as Hispanic. Black participants made up 7.7% of U.S. and Canadian cancer clinical drug trials and 2.6% of global cancer clinical drug trials while Asian participants made up 13.5% of global cancer clinical drug trials but only 1.8% of U.S. and Canadian cancer clinical drug trials. The current study indicates that although cancer clinical drug trials have become more inclusive of Asian participants, other racial and ethnic minority groups remain under-represented. This may result in an inadequate understanding of drug safety and efficacy in many racial and ethnic populations.
Asunto(s)
Ensayos Clínicos como Asunto , Neoplasias/epidemiología , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
BACKGROUND: Epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K) are involved in the proliferation and survival of many cancer types. Enhanced antitumor activity may be achieved through combined inhibition of these pathways. We report results for pictilisib (GDC-0941, a class I pan-PI3K inhibitor) plus erlotinib (an EGFR tyrosine kinase inhibitor) in patients with advanced solid tumors. MATERIALS AND METHODS: A 3 + 3 dose-escalation study was carried out at a starting daily dose of 60 mg pictilisib on days 1-21 of a 28-day cycle and 150 mg erlotinib from day 2 of cycle 1. The primary objectives of the study were to assess safety and tolerability, identify dose-limiting toxicities (DLTs), estimate the maximum tolerated dose, and identify the recommended phase II dose (RP2D). Evaluation of a dose-expansion cohort at the RP2D was performed. RESULTS: Fifty-seven patients were treated in the study. All patients experienced at least one adverse event (AE). Grade ≥3 AEs, serious AEs, and deaths were reported in 38 (66.7%), 19 (33.3%), and 4 (7.0%) patients, respectively. DLTs occurred in nine patients across eight cohorts and the RP2D was determined to be 340 mg pictilisib on a "5 days on, 2 days off" schedule plus 100 mg erlotinib. Two patients (3.5%) experienced partial response and 19 (33.3%) had stable disease. CONCLUSION: Combining pictilisib with erlotinib in patients with advanced solid tumors is feasible; however, antitumor activity is limited. Additional studies may identify patients likely to benefit from combined inhibition of EGFR and PI3K pathways. IMPLICATIONS FOR PRACTICE: Combining drugs targeting different signaling pathways in cancer growth and survival could overcome drug resistance and improve antitumor activity. In this first-in-human study for the combination, addition of the PI3K inhibitor pictilisib to the EGFR tyrosine kinase inhibitor erlotinib resulted in toxicity that led to dose and schedule modifications to identify a tolerable recommended phase II dose of 340 mg pictilisib on a "5 days on, 2 days off" schedule plus 100 mg erlotinib daily. The limited antitumor activity observed, however, suggests that additional studies are needed to identify patients most likely to benefit from combined EGFR and PI3K inhibition.
Asunto(s)
Receptores ErbB/genética , Clorhidrato de Erlotinib/administración & dosificación , Indazoles/administración & dosificación , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Sulfonamidas/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Proliferación Celular/genética , Relación Dosis-Respuesta a Droga , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib/efectos adversos , Clorhidrato de Erlotinib/farmacocinética , Femenino , Humanos , Indazoles/efectos adversos , Indazoles/farmacocinética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/genética , Neoplasias/patología , Fosfatidilinositol 3-Quinasas/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinéticaRESUMEN
Expression of Sprouty genes is frequently decreased or absent in human prostate cancer, implicating them as suppressors of tumorigenesis. Here we show they function in prostate tumor suppression in the mouse. Concomitant inactivation of Spry1 and Spry2 in prostate epithelium causes ductal hyperplasia and low-grade prostatic intraepithelial neoplasia (PIN). However, when Spry1 and Spry2 loss-of-function occurs in the context of heterozygosity for a null allele of the tumor suppressor gene Pten, there is a striking increase in PIN and evidence of neoplastic invasion. Conversely, expression of a Spry2 gain-of-function transgene in Pten null prostatic epithelium suppresses the tumorigenic effects of loss of Pten function. We show that Sprouty gene loss-of-function results in hyperactive RAS/ERK1/2 signaling throughout the prostate epithelium and cooperates with heterozygosity for a Pten null allele to promote hyperactive PI3K/AKT signaling. Furthermore, Spry2 gain-of-function can suppress hyperactivation of AKT caused by the absence of PTEN. Together, these results point to a key genetic interaction between Sprouty genes and Pten in prostate tumorigenesis and provide strong evidence that Sprouty genes can function to modulate signaling via the RAS/ERK1/2 and PI3K/AKT pathways. The finding that Sprouty genes suppress tumorigenesis caused by Pten loss-of-function suggests that therapeutic approaches aimed at restoring normal feedback mechanisms triggered by receptor tyrosine kinase signaling, including Sprouty gene expression, may provide an effective strategy to delay or prevent high-grade PIN and invasive prostate cancer.
Asunto(s)
Genes Supresores de Tumor/fisiología , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas de la Membrana/fisiología , Fosfohidrolasa PTEN/metabolismo , Fosfoproteínas/fisiología , Neoplasia Intraepitelial Prostática/genética , Proteínas Adaptadoras Transductoras de Señales , Animales , Cartilla de ADN/genética , Técnica del Anticuerpo Fluorescente , Técnicas Histológicas , Hibridación in Situ , Péptidos y Proteínas de Señalización Intracelular , Captura por Microdisección con Láser , Masculino , Proteínas de la Membrana/deficiencia , Ratones , Fosfohidrolasa PTEN/genética , Fosfoproteínas/deficiencia , Reacción en Cadena de la Polimerasa , Neoplasia Intraepitelial Prostática/fisiopatología , Proteínas Serina-Treonina Quinasas , Proteínas ras/metabolismoRESUMEN
PURPOSE: To inform prognosis, treatment response, disease biology, and KRAS G12C mutation heterogeneity, we conducted exploratory circulating tumor DNA (ctDNA) profiling on 134 patients with solid tumors harboring a KRAS G12C mutation treated with single-agent divarasib (GDC-6036) in a phase 1 study. EXPERIMENTAL DESIGN: Plasma samples were collected for serial ctDNA profiling at baseline (Cycle 1 Day 1 prior to treatment) and multiple on-treatment time points (Cycle 1 Day 15 and Cycle 3 Day 1). RESULTS: KRAS G12C ctDNA was detectable from plasma samples in 72.9% (43/59) and 92.6% (50/54) of patients with non-small cell lung cancer and colorectal cancer, respectively, the majority of whom were eligible for study participation based on a local test detecting the KRAS G12C mutation in tumor tissue. Baseline ctDNA tumor fraction was associated with tumor type, disease burden, and metastatic sites. A decline in ctDNA level was observed as early as Cycle 1 Day 15. Serial assessment showed a decline in ctDNA tumor fraction associated with response and progression-free survival. Except for a few cases of KRAS G12C sub-clonality, on-treatment changes in KRAS G12C variant allele frequency mirrored changes in the overall ctDNA tumor fraction. CONCLUSION: Across tumor types, the KRAS G12C mutation likely represents a truncal mutation in the majority of patients. Rapid and deep decline in ctDNA tumor fraction was observed in patients responding to divarasib treatment. Early on-treatment dynamics of ctDNA were associated with patient outcomes and tumor response to divarasib treatment.
RESUMEN
Racial/ethnic disparities mar NSCLC care and treatment outcomes. While socioeconomic factors and access to healthcare are important drivers of NSCLC disparities, a deeper understanding of genetic ancestry-associated genomic landscapes can better inform the biology and the treatment actionability for these tumors. We present a comprehensive ancestry-based prevalence and co-alteration landscape of genomic alterations and immunotherapy-associated biomarkers in patients with KRAS and EGFR-altered non-squamous (non-Sq) NSCLC. KRAS was the most frequently altered oncogene in European (EUR) and African (AFR), while EGFR alterations predominated in East Asian (EAS), South Asian (SAS), and Admixed American (AMR) groups, consistent with prior studies. As expected, STK11 and KEAP1 alterations co-occurred with KRAS alterations while showing mutual exclusivity with EGFR alterations. EAS and AMR KRAS-altered non-Sq NSCLC showed lower rates of co-occurring STK11 and KEAP1 alterations relative to other ancestry groups. Ancestry-specific co-alterations included the co-occurrence of KRAS and GNAS alterations in AMR, KRAS, and ARID1A alterations in SAS, and the mutual exclusivity of KRAS and NF1 alterations in the EUR and AFR ancestries. Contrastingly, EGFR-altered tumors exhibited a more conserved co-alteration landscape across ancestries. AFR exhibited the highest tumor mutational burden, with potential therapeutic implications for these tumors.
RESUMEN
KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.ClinicalTrials.gov identifier: NCT04449874.
Asunto(s)
Neoplasias Colorrectales , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Cetuximab/efectos adversos , Cetuximab/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Receptores ErbB/genética , Supervivencia sin Progresión , Mutación/genéticaRESUMEN
Recent clinical development of KRAS inhibitors has heightened interest in the genomic landscape of KRAS-altered cancers. We performed a pan-cancer analysis of KRAS-altered samples from 426,706 adult patients with solid or hematologic malignancies using comprehensive genomic profiling; additional analyses included 62,369 liquid biopsy and 7241 pediatric samples. 23% of adult pan-cancer samples had KRAS alterations; 88% were mutations, most commonly G12D/G12V/G12C/G13D/G12R, and prevalence was similar in liquid biopsies. Co-alteration landscapes were largely similar across KRAS mutations but distinct from KRAS wild-type, though differences were observed in some tumor types for tumor mutational burden, PD-L1 expression, microsatellite instability, and other mutational signatures. Prognosis of KRAS-mutant versus other genomic cohorts of lung, pancreatic, and colorectal cancer were assessed using a real-world clinicogenomic database. As specific KRAS inhibitors and combination therapeutic strategies are being developed, genomic profiling to understand co-alterations and other biomarkers that may modulate response to targeted or immunotherapies will be imperative.
RESUMEN
AIM: The phosphatidylinositol 3-kinase (PI3K) pathway is a potential therapeutic target in non-small cell lung cancer (NSCLC). This study aimed to evaluate the pan-PI3K inhibitor pictilisib in combination with first-line treatment regimens that were the standard of care at the time of study, in patients with NSCLC. PATIENTS AND METHODS: A 3 + 3 dose-escalation study was performed using a starting daily dose of 60 mg pictilisib on days 1-14 of a 21-day cycle. Depending on bevacizumab eligibility and NSCLC histology, patients also received either paclitaxel + carboplatin or pemetrexed + cisplatin, ± bevacizumab every 3 weeks. The primary objectives of the study were to assess safety and tolerability and to identify dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D), for each combination. RESULTS: All 66 treated patients experienced at least one adverse event (AE). Grade ≥III AEs, serious AEs and deaths occurred in 57 (86.4%), 56 (84.8%) and 9 (13.6%) patients, respectively. Three patients reported DLTs across the four arms of the study. The MTD was not reached in any arm and the RP2D of pictilisib was determined to be 330 mg (capsules) or 340 mg (tablets) on a '14 days on, 7 days off' schedule. The best confirmed response was partial response in 29 (43.9%) patients and stable disease in 20 (30.9%) patients. CONCLUSION: Combining pictilisib with various standard-of-care first-line treatment regimens is feasible from a safety perspective in patients with NSCLC, and encouraging preliminary anti-tumour activity was observed.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/administración & dosificación , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/administración & dosificación , Indazoles/administración & dosificación , Indazoles/farmacocinética , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/administración & dosificación , Pemetrexed/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Carboplatino/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/efectos adversos , Esquema de Medicación , Cálculo de Dosificación de Drogas , Femenino , Humanos , Indazoles/efectos adversos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/efectos adversos , Pemetrexed/efectos adversos , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/efectos adversos , Sulfonamidas/efectos adversos , Resultado del TratamientoRESUMEN
Purpose: Chk1 inhibition potentiates DNA-damaging chemotherapy by overriding cell-cycle arrest and genome repair. This phase I study evaluated the Chk1 inhibitor GDC-0425 given in combination with gemcitabine to patients with advanced solid tumors.Experimental Design: Patients received GDC-0425 alone for a 1-week lead-in followed by 21-day cycles of gemcitabine plus GDC-0425. Gemcitabine was initially administered at 750 mg/m2 (Arm A), then increased to 1,000 mg/m2 (Arm B), on days 1 and 8 in a 3 + 3 + 3 dose escalation to establish maximum tolerated dose (MTD). GDC-0425 was initially administered daily for three consecutive days; however, dosing was abbreviated to a single day on the basis of pharmacokinetics and tolerability. TP53 mutations were evaluated in archival tumor tissue. On-treatment tumor biopsies underwent pharmacodynamic biomarker analyses.Results: Forty patients were treated with GDC-0425. The MTD of GDC-0425 was 60 mg when administered approximately 24 hours after gemcitabine 1,000 mg/m2 Dose-limiting toxicities included thrombocytopenia (n = 5), neutropenia (n = 4), dyspnea, nausea, pyrexia, syncope, and increased alanine aminotransferase (n = 1 each). Common related adverse events were nausea (48%); anemia, neutropenia, vomiting (45% each); fatigue (43%); pyrexia (40%); and thrombocytopenia (35%). The GDC-0425 half-life was approximately 15 hours. There were two confirmed partial responses in patients with triple-negative breast cancer (TP53-mutated) and melanoma (n = 1 each) and one unconfirmed partial response in a patient with cancer of unknown primary origin.Conclusions: Chk1 inhibition with GDC-0425 in combination with gemcitabine was tolerated with manageable bone marrow suppression. The observed preliminary clinical activity warrants further investigation of this chemopotentiation strategy. Clin Cancer Res; 23(10); 2423-32. ©2016 AACR.