ABSTRACT
PURPOSE: Precision oncology clinical trials often struggle to accrue, partly because it is difficult to find potentially eligible patients at moments when they need new treatment. We piloted deployment of artificial intelligence tools to identify such patients at a large academic cancer center. PATIENTS AND METHODS: Neural networks that process radiology reports to identify patients likely to start new systemic therapy were applied prospectively for patients with solid tumors that had undergone next-generation sequencing at our center. Model output was linked to the MatchMiner tool, which matches patients to trials using tumor genomics. Reports listing genomically matched patients, sorted by probability of treatment change, were provided weekly to an oncology nurse navigator (ONN) coordinating recruitment to nine early-phase trials. The ONN contacted treating oncologists when patients likely to change treatment appeared potentially trial-eligible. RESULTS: Within weekly reports to the ONN, 60,199 patient-trial matches were generated for 2,150 patients on the basis of genomics alone. Of these, 3,168 patient-trial matches (5%) corresponding to 525 patients were flagged for ONN review by our model, representing a 95% reduction in review compared with manual review of all patient-trial matches weekly. After ONN review for potential eligibility, treating oncologists for 74 patients were contacted. Common reasons for not contacting treating oncologists included cases where patients had already decided to continue current treatment (21%); the trial had no slots (14%); or the patient was ineligible on ONN review (12%). Of 74 patients whose oncologists were contacted, 10 (14%) had a consult regarding a trial and five (7%) enrolled. CONCLUSION: This approach facilitated identification of potential patients for clinical trials in real time, but further work to improve accrual must address the many other barriers to trial enrollment in precision oncology research.
Subject(s)
Neoplasms , Humans , Neoplasms/drug therapy , Neoplasms/genetics , Artificial Intelligence , Precision Medicine , Medical Oncology , Pilot ProjectsABSTRACT
BACKGROUND: In this phase Ib/II open-label study, tumor immune suppression was targeted in patients with advanced refractory solid tumors and patients with recurrent/refractory non-small cell lung cancer (NSCLC) using galunisertib with nivolumab. METHODS: Eligible patients were ≥ 18 years old, had an Eastern Cooperative Oncology Group performance status ≤ 1, and were treatment-naive for anti-programmed cell death-1, its ligand, or transforming growth factor ß receptor 1 kinase inhibitors. Phase Ib was an open-label, dose-escalation assessment of the safety and tolerability of galunisertib with nivolumab in patients with advanced refractory solid tumors. Phase II evaluated the safety of galunisertib with nivolumab in NSCLC patients who had received prior platinum-based treatment but were immuno-oncology agent-naive. RESULTS: This trial was conducted between October 2015 and August 2020. No dose-limiting toxicities were observed in phase I. In the phase II NSCLC cohort (n = 25), patients received 150 mg twice daily galunisertib (14 days on/14 days off dosing schedule for all phases) plus nivolumab at 3 mg/kg (intravenously every 2 weeks). In this phase, the most frequent treatment-related adverse events (AEs) were pruritus (n = 9, 36%), fatigue (n = 8, 32%), and decreased appetite (n = 7, 28%). No grade 4 or 5 treatment-related AEs were observed. Six (24%) patients had confirmed partial response (PR) and 4 (16%) had stable disease; 1 additional patient had confirmed PR after initial pseudo-progression. The median duration of response was 7.43 months (95% confidence interval [CI]: 3.75, NR). Among the 7 responders, including the delayed responder, 1 had high PD-L1 expression (≥ 50%). The median progression-free survival was 5.26 months (95% CI: 1.77, 9.20) and the median overall survival was 11.99 months (95% CI: 8.15, NR). Interferon gamma response genes were induced post-treatment and cell adhesion genes were repressed, although the association of these observations with tumor response and clinical outcomes was not statistically powered due to limited samples available. CONCLUSIONS: The study met its primary endpoint as galunisertib combined with nivolumab was well tolerated. Preliminary efficacy was observed in a subset of patients in the Phase 2 NSCLC cohort. TRIAL REGISTRATION: Trial registered with ClinicalTrials.gov (NCT02423343; 22.04.2015).
Subject(s)
Antineoplastic Agents, Immunological , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Adolescent , Humans , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/etiology , Lung Neoplasms/pathology , Neoplasm Recurrence, Local/drug therapy , Nivolumab/therapeutic useABSTRACT
PURPOSE: A novel, selective, next-generation transforming growth factor beta (TGFß) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer. PATIENTS AND METHODS: This phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (LY3200882, gemcitabine, and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin, and radiation). RESULTS: Overall, 139 patients with advanced cancer were treated. The majority (93.5%) of patients experienced ≥1 treatment-emergent adverse events (TEAE), with 39.6% LY3200882-related. Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the pancreatic cancer arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in two schedules: 50 mg twice a day 2-weeks-on/2-weeks-off and 35 mg twice a day 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable Revised Assessment in Neuro Oncology (RANO) partial responses (PR) with LY3200882 monotherapy (n = 3) or LY3200882-LY3300054 combination therapy (n = 1). In treatment-naïve patients with advanced pancreatic cancer, 6 of 12 patients achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 PR and 3 of 12 patients demonstrated stable disease, for an overall 75% disease-control rate with the combination of LY3200882, gemcitabine, and nab-paclitaxel. CONCLUSIONS: LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in pancreatic cancer. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced pancreatic cancer are warranted.
Subject(s)
Antineoplastic Agents , Head and Neck Neoplasms , Pancreatic Neoplasms , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Humans , Maximum Tolerated Dose , Paclitaxel/therapeutic use , Pancreatic Neoplasms/drug therapy , Transforming Growth Factor betaABSTRACT
PURPOSE: Immune checkpoint inhibitors show high response rates and durable clinical benefit in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) tumors. However, 50%-60% do not respond to single-agent anti-programmed death-1/programmed death ligand 1 (PD-1/PD-L1) antibodies, and approximately 50% of responders relapse within 6-12 months. This phase Ib trial evaluated safety and antitumor activity of anti-PD-L1 antibody LY3300054 monotherapy or in combination with anti-TIM-3 antibody LY3321367 in patients with MSI-H/dMMR advanced solid tumors. PATIENTS AND METHODS: Eligible patients ≥18 years without prior anti-PD-1/PD-L1 therapy received LY3300054 monotherapy (N = 40) or combination (N = 20); patients with PD-1/PD-L1 inhibitor-resistant/refractory tumors received the combination (N = 22). LY3300054 (700 mg) and anti-TIM-3 antibody (cycles 1-2: 1,200 mg, cycle 3 onward: 600 mg) were administered intravenously every 2 weeks. Primary endpoints were safety and tolerability. RESULTS: Eighty-two patients were enrolled. Most had colorectal (n = 39, 47.6%) or endometrial (n = 14, 17.1%) tumors. More than 70% of patients in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort had received ≥3 treatment lines. Treatment-related adverse events (TRAE) occurred in 22 patients (55.0%) receiving monotherapy, 13 (65.0%) in the PD-1/PD-L1 inhibitor-naïve combination cohort, and 6 (27.3%) in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort. A total of 2 patients (5.0%) receiving monotherapy and 3 (7.1%) receiving the combination experienced grade ≥3 TRAEs. Objective responses occurred in 13 patients (32.5%) with monotherapy, 9 (45.0%) in the PD-1/PD-L1 inhibitor-naïve combination cohort, and 1 patient (4.5%) in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort. CONCLUSIONS: LY3300054 monotherapy and combined LY3300054/anti-TIM-3 had manageable safety profiles. Both regimens showed promising clinical activity against PD-1/PD-L1 inhibitor-naïve MSI-H/dMMR tumors. The combination had limited clinical benefit in patients with PD-1/PD-L1 inhibitor-resistant/refractory MSI-H/dMMR tumors.
Subject(s)
B7-H1 Antigen , Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , B7-H1 Antigen/adverse effects , DNA Mismatch Repair , Hepatitis A Virus Cellular Receptor 2/therapeutic use , Humans , Microsatellite Instability , Neoplasms/drug therapy , Neoplasms/geneticsABSTRACT
LY3381916 is an orally available, highly selective, potent inhibitor of indoleamine 2,3-dioxygenase 1. This study explored the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of LY3381916 monotherapy and in combination with a programmed death-ligand 1 (PD-L1) inhibitor (LY3300054) in patients with advanced solid tumors. During dose escalation, patients received escalating doses of LY3381916 at 60-600 mg once daily (qd) and 240 mg twice daily in monotherapy (n=21) and in combination with PD-L1 inhibitor at 700 mg every 2 weeks (n=21). A modified toxicity probability interval method was used to guide dose escalation. Dose-limiting toxicities occurred in 3 patients; 1 at LY3381916 240 mg twice daily (alanine aminotransferase/aspartate aminotransferase increase and systemic inflammatory response syndrome) and 2 at LY3381916 240 mg qd in combination with PD-L1 inhibitor (fatigue and immune-related hepatitis). LY3381916, at the recommended phase II dose, 240 mg qd, in combination with PD-L1 inhibitor, produced maximal inhibition of indoleamine 2,3-dioxygenase 1 activity in plasma and tumor tissue, and led to an increase of CD8 T cells in tumor tissue. In the combination dose expansion cohorts, 14 triple-negative breast cancer and 4 non-small cell lung cancer patients were enrolled. Treatment-related liver toxicity (grade ≥2 alanine aminotransferase/aspartate aminotransferase increase or immune-related hepatitis) was the most prominent adverse event in triple-negative breast cancer patients (n=5, 35.7%). Best response was stable disease. These preliminary data suggest an alternative dose level of LY3381916 is needed for the combination with PD-L1 inhibitor. The combination clinical activity was limited in this study.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , B7-H1 Antigen , Carcinoma, Non-Small-Cell Lung , Indoleamine-Pyrrole 2,3,-Dioxygenase , Lung Neoplasms , Triple Negative Breast Neoplasms , Adult , Aged , Female , Humans , Male , Middle Aged , Young Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , B7-H1 Antigen/antagonists & inhibitors , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Indoleamine-Pyrrole 2,3,-Dioxygenase/blood , Kynurenine/blood , Lung Neoplasms/blood , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Triple Negative Breast Neoplasms/blood , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/metabolismABSTRACT
BACKGROUND: We assessed the safety, efficacy, and pharmacokinetics of the transforming growth factor beta (TGFß) receptor inhibitor galunisertib co-administered with the anti-programmed death-ligand 1 (PD-L1) antibody durvalumab in recurrent/refractory metastatic pancreatic cancer previously treated with ≤2 systemic regimens. METHODS: This was a two-part, single-arm, multinational, phase Ib study. In a dose-finding phase, escalating oral doses of galunisertib were co-administered on days 1-14 with fixed-dose intravenous durvalumab 1500 mg on day 1 every 4 weeks (Q4W), followed by an expansion cohort phase. RESULTS: The galunisertib recommended phase II dose (RP2D) when co-administered with durvalumab 1500 mg Q4W was 150 mg two times per day. No dose-limiting toxicities were recorded. Among 32 patients treated with galunisertib RP2D, 1 patient had partial response, 7 had stable disease, 15 had objective progressive disease, and 9 were not evaluable. Disease control rate was 25.0%. Median overall survival and progression-free survival were 5.72 months (95% CI: 4.01 to 8.38) and 1.87 months (95% CI: 1.58 to 3.09), respectively. Pharmacokinetic profiles for combination therapy were comparable to those published for each drug. There was no association between potential biomarkers and treatment outcomes. CONCLUSION: Galunisertib 150 mg two times per day co-administered with durvalumab 1500 mg Q4W was tolerable. Clinical activity was limited. Studying this combination in patients in an earlier line of treatment or selected for predictive biomarkers of TGFß inhibition might be a more suitable approach. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02734160.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Immune Checkpoint Inhibitors/therapeutic use , Pancreatic Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Quinolines/therapeutic use , Receptor, Transforming Growth Factor-beta Type I/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , B7-H1 Antigen/metabolism , Disease Progression , Europe , Female , Humans , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/pharmacokinetics , Male , Middle Aged , Neoplasm Metastasis , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Progression-Free Survival , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/adverse effects , Pyrazoles/pharmacokinetics , Quinolines/adverse effects , Quinolines/pharmacokinetics , Receptor, Transforming Growth Factor-beta Type I/metabolism , Republic of Korea , Signal Transduction , Time Factors , United StatesABSTRACT
PURPOSE: T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) blunts anticancer immunity and mediates resistance to programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors. We assessed a novel, first-in-class, TIM-3 mAb, LY3321367, alone or in combination with the anti-PD-L1 antibody, LY300054 in patients with advanced solid tumor. PATIENTS AND METHODS: This open-label, multicenter, phase Ia/b study aimed to define the safety/tolerability and recommended phase II dose (RP2D) of LY3321367 with or without LY300054. Secondary objectives included pharmacokinetics/pharmacodynamics, immunogenicity, and efficacy. Biomarkers were assessed in exploratory analysis. RESULTS: No dose-limiting toxicities were observed in the monotherapy (N = 30) or combination (N = 28) dose escalation. LY3321367 treatment-related adverse events (≥2 patients) included pruritus, rash, fatigue, anorexia, and infusion-related reactions. Dose-proportional increase in LY3321367 concentrations was not affected by either LY300054 or antidrug antibodies (observed in 50%-70% of patients). Pharmacokinetic/pharmacodynamic modeling indicated 100% target engagement at doses ≥600 mg. LY3321367 RP2D was 1,200 mg biweekly for four doses followed by 600 mg every 2 weeks thereafter. In the non-small cell lung cancer monotherapy expansion cohort, outcomes varied by prior anti-PD-1 therapy response status: anti-PD-1/L1 refractory patients [N = 23, objective response rate (ORR) 0%, disease control rate (DCR) 35%, progression-free survival (PFS) 1.9 months] versus anti-PD-1/L1 responders (N = 14, ORR 7%, DCR 50%, PFS 7.3 months). In combination expansion cohorts (N = 91), ORR and DCR were 4% and 42%; CD8 infiltration in paired biopsies increased in approximately half these patients. CONCLUSIONS: LY3321367 exhibited acceptable safety profile with favorable pharmacokinetics/pharmacodynamics but only modest antitumor activity. The therapeutic relevance of TIM-3 blockade requires further investigation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Hepatitis A Virus Cellular Receptor 2 , Immune Checkpoint Inhibitors , Neoplasms , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Young Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , B7-H1 Antigen/antagonists & inhibitors , Dose-Response Relationship, Drug , Hepatitis A Virus Cellular Receptor 2/antagonists & inhibitors , Immune Checkpoint Inhibitors/administration & dosage , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/pharmacokinetics , Neoplasm Staging , Neoplasms/diagnosis , Neoplasms/drug therapy , Neoplasms/immunology , Neoplasms/mortality , Progression-Free Survival , Response Evaluation Criteria in Solid TumorsABSTRACT
PURPOSE: Investigate the safety and efficacy of LY3415244, a TIM-3/PD-L1 bispecific antibody that blocks TIM-3 and PD-L1 in patients with advanced solid tumors. PATIENTS AND METHODS: A phase I, multicenter, open-label study was conducted in patients with advanced solid tumors. Patients were dosed every 2 weeks intravenously with flat doses of LY3415244 escalating from 3 to 70 mg. The primary endpoints were safety, tolerability, and identification of the recommended phase II dose. RESULTS: Between November 2018 and October 2019, 12 patients were enrolled into four cohorts and received at least one dose of LY3415244. Two patients (16.7%) developed clinically significant anaphylactic infusion-related reactions and all patients developed treatment-emergent antidrug antibodies (TE-ADA). ADA titers were sometimes very high and negatively impacted soluble TIM-3 target engagement in most patients. ADA epitope specificity was against both TIM-3 and PD-L1 arms of the bispecific antibody; most TE-ADAs initially targeted the TIM-3 arm after the first dose. Preexisting ADAs against LY3415244 were also detected in normal (unexposed) human serum samples. One patient with PD-1 refractory non-small cell lung cancer had a near partial response (-29.6%). CONCLUSIONS: This TIM-3 and PD-L1 bispecific format was associated with unexpected immunogenicity targeting both arms of the bispecific antibody, resulting in early study termination. Epitope specificity analysis revealed an initial response toward the TIM-3 arm and presence of preexisting ADAs to the bispecific molecule in the general population. This experience emphasizes the importance of thorough analyses for preexisting ADAs as part of immunogenicity risk assessment of novel antibodies.See related commentary by de Spéville and Moreno, p. 2669.
Subject(s)
Antibodies, Bispecific/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Hepatitis A Virus Cellular Receptor 2/antagonists & inhibitors , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Bispecific/pharmacology , Antineoplastic Agents, Immunological/pharmacology , Biomarkers , Disease Management , Drug Administration Schedule , Drug Monitoring , Female , Humans , Male , Middle Aged , Molecular Targeted Therapy/methods , Neoplasms/diagnosis , Neoplasms/etiology , Neoplasms/mortality , Treatment OutcomeABSTRACT
INTRODUCTION: Checkpoint inhibitors (CPIs) have been approved to treat metastatic NSCLC. Pegilodecakin + CPI suggested promising efficacy in phase 1 IVY, providing rationale for randomized phase 2 trials CYPRESS 1 and CYPRESS 2. METHODS: CYPRESS 1 (N = 101) and CYPRESS 2 (N = 52) included Eastern Cooperative Oncology Group performance status of 0 to 1 and first-line/second-line metastatic NSCLC, respectively, without known EGFR/ALK mutations. Patients were randomized 1:1; control arms received pembrolizumab (CYPRESS 1) or nivolumab (CYPRESS 2); experimental arms received pegilodecakin + CPI. Patients had programmed death-ligand 1 tumor proportion score of greater than or equal to 50% (CYPRESS 1) or 0% to 49% (CYPRESS 2). Primary end point was objective response rate (ORR) per investigator. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. Exploratory end points included immune activation biomarkers. RESULTS: Median follow-up for CYPRESS 1 and CYPRESS 2 was 10.0 and 11.6 months, respectively. Results for pegilodecakin + pembrolizumab versus pembrolizumab were as follows: ORR per investigator 47% versus 44% (OR = 1.1, 95% confidence interval [CI]: 0.5-2.5); median PFS 6.3 versus 6.1 months (hazard ratio [HR] = 0.937, 95% CI: 0.54-1.625); and median OS 16.3 months versus not reached (HR = 1.507, 95% CI: 0.708-3.209). Results per blinded independent central review were consistent. Treatment discontinuation rate owing to adverse events (AEs) doubled in the experimental arm (32% versus 15%). AEs with grade greater than or equal to 3 treatment-related AEs (62% versus 19%) included anemia (20% versus 0%) and thrombocytopenia (12% versus 2%). Results for pegilodecakin + nivolumab versus nivolumab were as follows: ORR per investigator 15% versus 12% (OR = 1.2, 95% CI: 0.3-5.9); median PFS 1.9 versus 1.9 months (HR = 1.006, 95% CI: 0.519-1.951); and median OS 6.7 versus 10.7 months (HR = 1.871, 95% CI: 0.772-4.532). AEs with grade greater than or equal to 3 treatment-related AEs (70.4% versus 16.7%) included anemia (40.7% versus 0%), fatigue (18% versus 0%), and thrombocytopenia (14.8% versus 0%). Biomarker data suggested activation of immunostimulatory signals of interleukin-10R pathway in pegilodecakin-containing arms. CONCLUSIONS: Despite evidence of biological effect in peripheral blood, adding pegilodecakin to CPI did not improve ORR, PFS, or OS, in first-line/second-line NSCLC. Pegilodecakin + CPI has been found to have overall higher toxicity compared with CPI alone, leading to doubling of treatment discontinuation rate owing to AEs.
Subject(s)
Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms , Antineoplastic Combined Chemotherapy Protocols , Humans , Interleukin-10 , Lung Neoplasms/drug therapy , Polyethylene Glycols/therapeutic useABSTRACT
PURPOSE: This phase Ia/Ib PACT study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of a new programmed cell death ligand 1 (PD-L1) inhibitor, LY3300054, as monotherapy or in combination with ramucirumab, abemaciclib, or merestinib (a type II MET kinase inhibitor) in patients with advanced, refractory solid tumors (NCT02791334). PATIENTS AND METHODS: Patients were enrolled into cohorts of escalating LY3300054 dose (phase Ia) as monotherapy (N = 15) or combined with ramucirumab (N = 10), abemaciclib (N = 24), or merestinib (N = 12). The phase Ib dose expansion enrolled 8 patients with melanoma in the monotherapy arm and 12 patients with pancreatic cancer in the merestinib combination arm. Combination treatments were administered concurrently from day 1 of each cycle. A 14-day lead-in abemaciclib arm was also explored. Primary endpoints were dose-limiting toxicity (DLT) and safety. RESULTS: Treatment-related adverse events included fatigue and nausea in the monotherapy arm (13% for each), hypothyroidism (30%) in the ramucirumab arm, diarrhea (54%) in the abemaciclib arm, and nausea (25%) in the merestinib arm. DLTs associated with hepatoxicity were observed in 3 of 4 patients in the abemaciclib lead-in cohorts. No DLTs or grade 3 or 4 hepatoxicity were reported in the concurrent abemaciclib arm. Pharmacokinetic characteristics were comparable with other PD-L1 inhibitors. One patient in each arm experienced a partial response per RECIST v1.1 lasting ≥7 months. CONCLUSIONS: LY3300054 was well tolerated without unexpected safety concerns when administered alone or concurrently with ramucirumab, abemaciclib, or merestinib. Lead-in abemaciclib before combining with LY3300054 was not feasible due to hepatotoxicity. Durable clinical benefits were seen in all regimens.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Aminopyridines/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , B7-H1 Antigen/immunology , Benzimidazoles/administration & dosage , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Indazoles/administration & dosage , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/immunology , Neoplasms/pathology , Niacinamide/administration & dosage , Niacinamide/analogs & derivatives , Prognosis , RamucirumabABSTRACT
OBJECTIVES: Combination immunotherapy may result in improved antitumor activity compared with single-agent treatment. We report results from dose-finding and dose-expansion cohorts of the phase 1/2 KEYNOTE-021 study that evaluated combination therapy with antiâprogrammed death 1 (PD-1) antibody pembrolizumab plus antiâcytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody ipilimumab in patients with previously treated advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Eligibility criteria stipulated histologically/cytologically confirmed advanced NSCLC and treatment failure on ≥1 prior systemic therapy (platinum-based chemotherapy or targeted therapy for patients with EGFR/ALK aberrations). In the dose-finding cohort, patients initially received pembrolizumab 10 mg/kg plus ipilimumab 1 or 3 mg/kg once every 3 weeks for 4 cycles followed by pembrolizumab 10 mg/kg monotherapy for up to 2 years. Based on emerging published data, subsequent patients received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg. Objective response rate (ORR; primary efficacy endpoint) was assessed per RECIST version 1.1 by blinded, independent central review. Phase 2 hypothesis that ORR would be greater than the 20% rate for historical controls was evaluated using the exact binomial test. RESULTS: Fifty-one patients were enrolled; 71% received ≥2 prior lines of therapy. No dose-limiting toxicities occurred at any dose level. Among patients who received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg (n = 44), ORR was 30% (95% CI, 17%-45%), but not statistically significantly >20% (P = 0.0858). Median progression-free survival in this group was 4.1 (95% CI, 1.4-5.8) months; median overall survival was 10.9 (95% CI, 6.1-23.7) months. With pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg, incidences of treatment-related adverse events, grade 3-5 treatment-related adverse events, and immune-mediated adverse events and infusion reactions were 64%, 29%, and 42%, respectively. CONCLUSIONS: In patients with heavily pretreated advanced NSCLC, pembrolizumab plus ipilimumab showed evidence of antitumor activity, but was associated with meaningful toxicity.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Immunotherapy/methods , Ipilimumab/therapeutic use , Lung Neoplasms/drug therapy , Adult , Aged , CTLA-4 Antigen/antagonists & inhibitors , Carcinoma, Non-Small-Cell Lung/mortality , Cohort Studies , Drug Resistance, Neoplasm , Drug-Related Side Effects and Adverse Reactions , Female , Humans , Lung Neoplasms/mortality , Male , Middle Aged , Neoplasm Staging , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Survival AnalysisABSTRACT
PURPOSE: To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor. PATIENTS AND METHODS: This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1-3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks. RESULTS: A total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with FGFR fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day. CONCLUSIONS: Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.
Subject(s)
Benzimidazoles/therapeutic use , Gene Fusion , Mutation , Neoplasms/drug therapy , Pyrazoles/therapeutic use , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 2/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 3/antagonists & inhibitors , Adult , Aged , Benzimidazoles/pharmacokinetics , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/genetics , Neoplasms/pathology , Prognosis , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/pharmacokinetics , Receptor, Fibroblast Growth Factor, Type 1/genetics , Receptor, Fibroblast Growth Factor, Type 2/genetics , Receptor, Fibroblast Growth Factor, Type 3/genetics , Signal Transduction , Tissue DistributionABSTRACT
SCLC remains an aggressive, deadly cancer with only modest effect on survival from standard chemotherapy. However, with the advent of immunotherapy and comprehensive genomic and transcriptomic profiling, multiple new targets are showing promise in the clinical arena, and just recently programmed death ligand 1 inhibition has been shown to improve the efficacy of standard chemotherapy in extended-disease SCLC. Our increasing understanding of the interactions between different pathways will enable more tailored immunotherapy and targeted therapies based on specific biomarkers and rational combinations. Here we discuss the preclinical and clinical strides in 2017 and 2018 that put us on the threshold of a new era in therapeutics and will, it is hoped, translate into significant improvements in survival.
Subject(s)
Lung Neoplasms/epidemiology , Medical Oncology/standards , Small Cell Lung Carcinoma/epidemiology , Thoracic Neoplasms/epidemiology , History, 21st Century , HumansABSTRACT
INTRODUCTION: Cohort G of KEYNOTE-021 (NCT02039674) evaluated the efficacy and safety of pembrolizumab plus pemetrexed-carboplatin (PC) versus PC alone as first-line therapy for advanced nonsquamous NSCLC. At the primary analysis (median follow-up time 10.6 months), pembrolizumab significantly improved objective response rate (ORR) and progression-free survival (PFS); the hazard ratio (HR) for overall survival (OS) was 0.90 (95% confidence interval [CI]: 0.42â1.91). Herein, we present an updated analysis. METHODS: A total of 123 patients with previously untreated stage IIIB/IV nonsquamous NSCLC without EGFR and/or ALK receptor tyrosine kinase gene (ALK) aberrations were randomized 1:1 to four cycles of PC with or without pembrolizumab, 200 mg every 3 weeks. Pembrolizumab treatment continued for 2 years; maintenance pemetrexed was permitted in both groups. Eligible patients in the PC-alone group with radiologic progression could cross over to pembrolizumab monotherapy. p Values are nominal (one-sided p < 0.025). RESULTS: As of December 1, 2017, the median follow-up time was 23.9 months. The ORR was 56.7% with pembrolizumab plus PC versus 30.2% with PC alone (estimated difference 26.4% [95% CI: 8.9%â42.4%, p = 0.0016]). PFS was significantly improved with pembrolizumab plus PC versus PC alone (HR = 0.53, 95% CI: 0.33â0.86, p = 0.0049). A total of 41 patients in the PC-alone group received subsequent antiâprogrammed death 1/antiâprogrammed death ligand 1 therapy. The HR for OS was 0.56 (95% CI: 0.32â0.95, p = 0.0151). Forty-one percent of patients in the pembrolizumab plus PC group and 27% in the PC-alone group had grade 3 to 5 treatment-related adverse events. CONCLUSIONS: The significant improvements in PFS and ORR with pembrolizumab plus PC versus PC alone observed in the primary analysis were maintained, and the HR for OS with a 24-month median follow-up was 0.56, favoring pembrolizumab plus PC.
Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/adverse effects , Carboplatin/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Pemetrexed/adverse effects , Pemetrexed/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carboplatin/pharmacology , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Pemetrexed/pharmacology , Progression-Free Survival , Survival Rate , Time FactorsABSTRACT
OBJECTIVES: Platinum-based chemotherapy for advanced non-small-cell lung cancer (NSCLC) has modest benefit overall, but has the potential to amplify immune responses. In cohorts A-C of the multicohort phase 1/2 study KEYNOTE-021 (Clinicaltrials.gov, NCT02039674), we evaluated combinations of platinum-doublet chemotherapy with the anti-programmed death 1 monocloncal antibody pembrolizumab. MATERIALS AND METHODS: Patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations were randomized to pembrolizumab 2 or 10 mg/kg Q3W plus carboplatin area under the serum concentration-time curve (AUC) 6 mg/mL/min plus paclitaxel 200 mg/m2 (cohort A, any histology), carboplatin AUC 6 mg/mL/min plus paclitaxel 200 mg/m2 plus bevacizumab 15 mg/kg (cohort B, non-squamous), or carboplatin AUC 5 mg/mL/min plus pemetrexed 500 mg/m2 (cohort C, non-squamous) for 4 cycles followed by maintenance pembrolizumab (cohort A), pembrolizumab plus bevacizumab (cohort B), or pembrolizumab plus pemetrexed (cohort C). Response was assessed by blinded independent central review. RESULTS: Overall, 74 patients were randomized; median follow-up was 21.4, 16.4, and 17.4 months in cohorts A, B, and C, respectively. No dose-limiting toxicities occurred in any cohort at either pembrolizumab dose. Most frequent treatment-related adverse events (AEs) were alopecia, fatigue, and nausea. Treatment-related grade 3/4 AEs occurred in 40%, 42%, and 46% of patients in cohorts A, B, and C, respectively; AEs with possible immune etiology occurred in 24%, 50%, and 38% of patients, respectively. Objective response rates were 48%, 56%, and 75% in cohorts A, B, and C, respectively. CONCLUSION: Pembrolizumab in combination with carboplatin-paclitaxel and with pemetrexed-carboplatin yielded encouraging antitumor activity and toxicity consistent with known toxicities of platinum-based chemotherapy or pembrolizumab monotherapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Bevacizumab/administration & dosage , Carboplatin/administration & dosage , Cohort Studies , Female , Humans , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Paclitaxel/administration & dosage , Pemetrexed/administration & dosageABSTRACT
BACKGROUND: This phase Ib study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of pimasertib (MSC1936369B), a MEK1/2 inhibitor, in combination with voxtalisib (SAR245409), a pan-PI3K and mTORC1/mTORC2 inhibitor, in patients with advanced solid tumours. METHODS: This study included a dose escalation and expansion in patients with select tumour types and alterations in the MAPK or PI3K pathways. A 3 + 3 design was used to determine MTD. Patients were evaluated for adverse events and tumour response. RESULTS: 146 patients were treated, including 63 in dose escalation and 83 in expansion. The MTD was pimasertib 90 mg and voxtalisib 70 mg daily. Based on the safety profile, the recommended phase 2 dose (RP2D) was pimasertib 60 mg and voxtalisib 70 mg. The most frequent treatment-emergent adverse events (TEAEs) were diarrhoea (75%), fatigue (57%), and nausea (50%). Responses included a complete response in one patient (1%), partial response in five (5%), and stable disease in 51 (46%). At the RP2D, 74 patients required dose interruption (73%), 20 required dose reduction (20%), and 26 discontinued treatment due to TEAEs (26%). CONCLUSIONS: The combination of pimasertib and voxtalisib showed poor long-term tolerability and limited anti-tumour activity in patients with advanced solid tumours.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Neoplasms/drug therapy , Niacinamide/analogs & derivatives , Phosphoinositide-3 Kinase Inhibitors , Quinoxalines/administration & dosage , Sulfonamides/administration & dosage , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Female , Humans , Male , Middle Aged , Niacinamide/administration & dosage , Niacinamide/adverse effects , Niacinamide/pharmacokinetics , Quinoxalines/adverse effects , Quinoxalines/pharmacokinetics , Sulfonamides/adverse effects , Sulfonamides/pharmacokineticsABSTRACT
INTRODUCTION: Atezolizumab, an anti-programmed death-ligand 1 (PD-L1) antibody, inhibits PD-L1:PD-1 and PD-L1:B7.1 interactions, restoring anticancer immunity. Here, we report final analyses from the non-small-cell lung cancer (NSCLC) cohort of the first atezolizumab phase I study. METHODS: Patients with NSCLC received atezolizumab 1-20 mg/kg or 1200 mg intravenously every 3 weeks. Baseline PD-L1 expression on tumour cells (TCs) and tumour-infiltrating immune cells (ICs) was assessed (VENTANA SP142 immunohistochemistry assay). Exploratory subgroup analyses investigated responses by baseline PD-L1 expression and oncogenic mutational status. RESULTS: Eighty-nine patients, 98% of whom had received previous systemic therapy, were evaluable for safety and antitumour activity. Atezolizumab was well tolerated, with grade III/IV treatment-related adverse events (TRAEs) observed in 10 patients (11%). All-grade TRAEs occurring in >10% of patients were fatigue, nausea and decreased appetite; grade III/IV TRAEs occurring in >2% of patients were fatigue, dyspnoea, hyponatremia and hypoxia. One patient died from treatment-unrelated pneumonia. Objective response rate (ORR) was 50% (95% confidence interval [CI], 28%-72%), 33% (20%-48%), 29% (18%-41%) and 11% (1%-35%) for the TC3 or IC3, TC2/3 or IC2/3, TC1/2/3 or IC1/2/3 and TC0 and IC0 subgroups, respectively. All-patient ORR was 23% (95% CI, 14%-33%). Median duration of response was 16.4 months (range, 7.2-53.4+). One-, 2-, and 3-year survival rates were 63% (95% CI, 53%-73%), 37% (26%-47%) and 28% (18%-38%), respectively. CONCLUSIONS: Single-agent atezolizumab was well tolerated with long-term clinical benefits, including durable responses and survival, in pretreated NSCLC. Improved responses and survival rates were seen with increasing baseline PD-L1 expression. CLINICALTRIALS. GOV IDENTIFIER: NCT01375842.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , B7-H1 Antigen/biosynthesis , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Fatigue/chemically induced , Female , Humans , Kaplan-Meier Estimate , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Male , Middle Aged , Nausea/chemically induced , Neoplasm Metastasis , Young AdultSubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Anaplastic Lymphoma Kinase , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/immunology , Clinical Trials as Topic , Drug Design , ErbB Receptors/genetics , Humans , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Molecular Targeted Therapy , Multicenter Studies as Topic , Pemetrexed/administration & dosage , Platinum/administration & dosage , Randomized Controlled Trials as Topic , Receptor Protein-Tyrosine Kinases/genetics , Treatment OutcomeABSTRACT
Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for over 85% of all cases. Until recently, chemotherapy - characterized by some benefit but only rare durable responses - was the only treatment option for patients with NSCLC whose tumors lacked targetable mutations. By contrast, immune checkpoint inhibitors have demonstrated distinctly durable responses and represent the advent of a new treatment approach for patients with NSCLC. Three immune checkpoint inhibitors, pembrolizumab, nivolumab and atezolizumab, are now approved for use in first- and/or second-line settings for selected patients with advanced NSCLC, with promising benefit also seen in patients with stage III NSCLC. Additionally, durvalumab following chemoradiation has been approved for use in patients with locally advanced disease. Due to the distinct features of cancer immunotherapy, and rapid progress in the field, clinical guidance is needed on the use of these agents, including appropriate patient selection, sequencing of therapies, response monitoring, adverse event management, and biomarker testing. The Society for Immunotherapy of Cancer (SITC) convened an expert Task Force charged with developing consensus recommendations on these key issues. Following a systematic process as outlined by the National Academy of Medicine, a literature search and panel voting were used to rate the strength of evidence for each recommendation. This consensus statement provides evidence-based recommendations to help clinicians integrate immune checkpoint inhibitors into the treatment plan for patients with NSCLC. This guidance will be updated following relevant advances in the field.