Efficacy of PD-1/PD-L1 inhibitors in the front-line setting as compared to previously treated patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20646-e20646
Author(s):  
Prantesh Jain ◽  
Monica Khunger ◽  
Vinay Pasupuleti ◽  
Adrian V Hernandez ◽  
Vamsidhar Velcheti
Keyword(s):  
Small Cell Lung Carcinoma ◽  
Single Agent ◽  
Objective Response ◽  
Clinical Activity ◽  
Cell Lung Carcinoma ◽  
Platinum Based Chemotherapy ◽  
Treatment Naïve ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Nsclc Patients

e20646 Background: Drugs targeting the PD-1/PD-L1 pathway show significant clinical activity in non-small cell lung carcinoma (NSCLC). Nivolumab, pembrolizumab and atezolizumab are currently approved for NSCLC patients who have progressed while on platinum-based chemotherapy. Recently, pembrolizumab received FDA approval for treatment naive NSCLC patients with tumor PD-L1 expression of ≥50%. However, there is relative lack of data on comparative efficacy of these drugs in the chemotherapy naive versus post-chemotherapy setting. In the current meta-analysis we compare the efficacy and toxicity of these drugs in chemotherapy naïve patients with those who receive them as subsequent therapy (after previous chemotherapy). Methods: A systematic search of electronic databases (PubMed-Medline, EMBASE, Scopus) and major conference proceedings was done for all clinical trials using PD1/PD-L1 inhibitors. Objective response rates (ORR) for patients determined to have positive tumor PD-L1 expression (Tumor Proportion Score ≥1%) from all phase I-III trials investigating nivolumab, pembrolizumab, atezolimumab, durvalumab and avelumab for NSCLC were collected. Only single agent PD-1/PDL-1 inhibitor trials were included. The ORR across trials was combined using DerSimonian-Laird random effects models. Higgins’ I2 statistic was used to assess heterogeneity. Results: 19 trials (7 with treatment naïve patients [n = 651]; 14 with chemotherapy treated patients [n = 2205]; 2 with separate treatment naïve and previously treated arms) were included. Treatment naïve patients were found to have statistically significant higher efficacy [ORR 28.27%(95% CI 20.70-36.52)] than those who received these drugs as subsequent therapy [ORR 20.13% (95%CI 17.53-22.85) (p = 0.02). Treatment naive patients had statistically significant higher rates of all grade pneumonitis as comapred to previously treated patients (4.9, 95%CI 3.4-6.7 vs 3.0 95% CI 2.0-4.1). Conclusions: PD1/PDL1 therapy for advanced NSCLC has a significantly improved efficacy (based on ORR) when used in treatment naïve patients as compared to its use in patients who have been previously treated with chemotherapy.

Incidence of pneumonitis with use of PD-1 and PD-L1 inhibitors in non-small cell lung cancer: A systematic review and meta-analysis of trials.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20647-e20647 ◽  
Author(s):  
Monica Khunger ◽  
Vinay Pasupuleti ◽  
Sagar Rakshit ◽  
Prantesh Jain ◽  
Peter J. Mazzone ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Single Agent ◽  
Small Cell ◽  
Clinical Activity ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Treatment Naïve ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3

e20647 Background: PD-1/PD-L1 inhibitors show clinical activity in non-small cell lung carcinoma (NSCLC). However, these agents are sometimes associated with potentially fatal immune related pneumonitis. Preliminary reports of trials suggest a difference in the rate of pneumonitis associated with PD-1 and PD-L1 inhibitors. In this meta-analysis, we sought to determine the overall incidence of pneumonitis, and differences by type of inhibitor and prior chemotherapy use. Methods:We systematically searched databases (PubMed-Medline, Embase, Scopus) and conference proceedings until December 2016 for clinical trials using PD-1/PD-L1 inhibitors. Rates of pneumonitis of any grade and grade 3 or higher from all phase I-III trials investigating nivolumab, pembrolizumab, atezolimumab, durvalumab and avelumab for NSCLC were collected. Only single agent PD-1/PDL-1 inhibitor trials were included. The incidence of pneumonitis across trials was calculated using DerSimonian-Laird random effects models. We compared incidences between PD-1 and PD-L1 inhibitors, as well as between treatment naïve and previously treated patients (pts). Results: 19 distinct published trials (12 with PD-1 inhibitors [n = 3232] and 7 with PD-L1 inhibitors [n = 1806]) were identified. PD-1 inhibitors were found to have statistically significant higher incidence of any grade pneumonitis as compared to PD-L1 inhibitors (3.6%, 95%CI 2.4%-4.9% vs 1.3%, 95%CI 0.8%-1.9%; p = 0.001). There was also a higher incidence of grade 3 or greater pneumonitis with PD-1 inhibitors (1.1%, 95%CI 0.6%-1.7% vs 0.4%, 95%CI 0%-0.8%, p = 0.02). Pts who received PD-1 or PD-L1 inhibitors in the front line setting experienced more grade 1-4 pneumonitis as compared to previously treated pts (4.3%, 95%CI 2.4%-6.3% vs 2.8%, 95%CI 1.7%- 4%, p = 0.03, however the rates of grade 3 or greater pneumonitis were not significantly different in treatment naïve and previously treated pts. Conclusions: Pneumonitis was more frequently associated with use of PD-1 inhibitors than PD-L1 inhibitors. There was a higher incidence of all grade pneumonitis with PD-1 inhibitors in treatment naïve patients as compared to previously treated patients.

Rucaparib for recurrent, locally advanced, or metastatic urothelial carcinoma (mUC): Results from ATLAS, a phase II open-label trial.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 440-440 ◽  
Author(s):  
Petros Grivas ◽  
Yohann Loriot ◽  
Susan Feyerabend ◽  
Rafael Morales-Barrera ◽  
Min Yuen Teo ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Previously Treated

440 Background: ATLAS (NCT03397394) evaluated the efficacy/safety of the PARP inhibitor (PARPi) rucaparib in patients (pts) with previously treated locally advanced/unresectable UC or mUC. Methods: Pts with measurable disease who had progressed after 1–2 prior regimens (ie, platinum-based chemotherapy [PBC] and/or immune checkpoint inhibitors [ICI]) were enrolled regardless of tumor homologous recombination deficiency (HRD) status. Prior PARPi was not allowed. Pts received rucaparib 600 mg PO BID. Baseline tumor tissue or archival tissue ≤6 mo without intervening therapy was required; serial circulating tumor DNA samples were collected. Primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (defined as genomic loss of heterozygosity ≥10%) populations. Key secondary endpoints: progression-free survival (PFS) and safety. Clinical benefit rate (CBR) was defined as complete or partial response or stable disease (SD) lasting ≥16 weeks. Results: As of Oct 7, 2019, 97 pts were enrolled (median age 66 y [range, 39–87]); most were men (n=76, 78.4%) and had ECOG PS 1 (n=65, 67.0%). Sixty-six pts (68.0%) had both prior PBC and ICI. Twenty pts (20.6%) were HRD-positive, 30 (30.9%) were HRD-negative and 47 (48.5%) had unknown HRD status; 4 pts had a deleterious BRCA1/2 alteration. Median time on treatment was 54 d (range, 2–224). There were no confirmed responses. Of 96 evaluable pts, 27 (28.1%) had a best response of SD; CBR was 12.5% and median PFS was 1.8 mo. No relationship was observed between HRD status and clinical activity. Treatment was discontinued by 93 pts (95.9%), mainly due to radiologic or clinical progression (73.1%). Most frequent any grade treatment-emergent (any cause) adverse events were asthenia/fatigue (n=56, 57.7%), nausea (n=40, 41.2%), and anemia (n=34, 35.1%). Conclusions: Single agent rucaparib did not show activity in pts with previously treated advanced UC and enrollment was suspended at the first interim analysis. The safety profile was consistent with that observed in pts with ovarian cancer. Next generation sequencing–based characterization of the genomic landscape of mUC will be presented. Clinical trial information: NCT03397394.

A Multicentre Phase II Study of the Aminopeptidase Inhibitor, CHR- 2797, in the Treatment of Elderly and/or Previously Treated patients with Acute Myeloid Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 961-961 ◽  
Author(s):  
B. Lowenberg ◽  
F. Davies ◽  
C. Müller-Tidow ◽  
Ulrich Dührsen ◽  
A. Burnett ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Single Agent ◽  
Clinical Activity ◽  
Open Label ◽  
Elderly Aml ◽  
Previously Treated Patients ◽  
Previously Treated

Abstract Tosedostat (TSD, CHR-2797) is an aminopeptidase inhibitor that selectively depletes amino acid pools in malignant cells, resulting in anti-proliferative, pro-apoptotic and antiangiogenic effects. In a phase I study, treatment with TSD resulted in complete remission in a number of refractory AML patients. The primary objective of this phase II study was to determine whether TSD was a sufficiently effective therapy to warrant pivotal studies. Methods. This was an open label, single agent, phase II study to assess clinical activity of TSD in elderly and/or previously treated patients with AML/MDS. Patients were treated with once daily oral doses of the maximum acceptable dose (130 mg) of TSD for up to 84 days. Further treatment was allowed if, in the opinion of the investigator, this was considered to be beneficial. Clinical responses were assessed by monthly bone marrow aspirates and weekly hematological assessments. Results. Of the 41 TSD-treated patients with AML (n=38) or MDS (n=3), who were enrolled between March and October 2007, 27 were male, 14 female, with a mean age of 67 years (range 34–82). The median performance status (ECOG) at baseline was 1 (range 0–2). Twelve (31.6%) AML patients and 2 (66.7%) MDS patients were chemotherapy naïve, and 9 (23.7%) AML patients had either secondary disease or adverse cytogenetics. For 16 (39%) patients, treatment with TSD was a second or later salvage attempt. Thirty two patients (30 AML, 2 MDS-RAEB1 and 2) received ≥28 days treatment, and 21 (51.2%) patients completed the formal 84-day study period (19 AML, 2 MDS). Nine (22%) of the patients (7 AML, 2 MDS) continued treatment with TSD after 84 days, and 6 (15%) patients were on TSD in total for more than 6 months (4 AML, 2 MDS). Ten (26.3%) of the AML patients responded to treatment; amongst these, 2 patients received TSD as 2nd/3rd salvage therapy, and a further 2 patients did not show a complete response (CR) after 2 previous induction courses of chemotherapy. Three AML patients achieved a CR (< 5% blasts in bone marrow), of whom 2 were in durable remission (232 days, continuing*; 171 days), and 7 had a partial response (PR, 5–15% blasts) lasting approximately 1–3 months. Two (66.7%) of the MDS patients also responded to treatment with TSD; these patients maintained stable disease for more than 6 months. All responders (CR, PR and SD) were >60 years at the time of the first dose. Median overall survival in AML patients was 130 days (range 8 – 478 days*). The most frequently reported adverse events were: fatigue (61%), thrombocytopenia (49%), pyrexia (39%), peripheral edema (39%) and diarrhea (34%); 9 (22%) patients withdrew due to drug related toxicity. TSD had no effect on hemoglobin or neutrophils. Conclusions. This study in patients with advanced AML/MDS with adverse prognosis demonstrates the anti-leukemic activity of TSD in elderly AML patients, as measured by CR and decreases in leukemic blasts. In addition, 2 relapsed high risk MDS patients achieved disease stabilization. TSD at 130mg qd is also very well tolerated over a long period of exposure (6–10 months). These results support further pivotal studies with TSD in elderly AML and MDS patients.

Phase II trial of gemcitabine and irinotecan in previously treated patients with small-cell lung cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7718-7718
Author(s):  
M. Nishio ◽  
F. Ohyanagi ◽  
A. Horikike ◽  
Y. Okano ◽  
Y. Satoh ◽  
...  
Keyword(s):  
Survival Time ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Performance Status ◽  
Single Agent ◽  
Refractory Disease ◽  
Platinum Based Chemotherapy ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3

7718 Background: Gemcitabine and irinotecan has been shown to have an antitumor activity as a single agent against previously treated SCLC. The objective of this study was to assess the efficacy and safety of gemcitabine combined with irinotecan in patients with refractory or relapsed SCLC. Methods: Patients with histologically or cytologically confirmed SCLC, 20 to 74 years in age, performance status 0–2, with a history of receiving one platinum-based chemotherapy were eligible for the study. Treatment consisted of gemcitabine (1,000 mg/m2) and irinotecan (150 mg/m2) on days 1 and 15 of a 28-day cycle.The primary endpoint was the response rate (RR), and planned sample size for this phase II study was 30 patients (Simon's two-stage minimax design). Results: Thirty-one patients were enrolled and 30 patients (24 males/6 females, 10 refractory/20 sensitive, median age, 65 years) receive protocol treatment in this phase II trial. The median treatment cycles were 3 (1–10). The overall response rates was obtained in 39.3% (95% CI: 18.1% to 60.5%) of the patients, including two patients with refractory disease and 9 patients with sensitive disease. The median overall survival time was 14.4 months, and the 1-year survival rate was 51%. The median survival time of the patients with refractory disease was 7.4 months, compared with 14.4 months for patients with sensitive disease. The chief grade 3/4 toxicities included neutropenia (42%), thrombocytopenia (3%), diarrhea (9%), and liver dysfunction (3%). The only grade 4 toxicities were one case of grade 4 neutropenia (3.3%) and one case of grade 4 thrombocytopenia (3.3%). Conclusion: Gemcitabine plus irinotecan is an active regimen that seems to be well- tolerated by patients with previously treated SCLC. No significant financial relationships to disclose.

Impact and correlation of mutational load (ML) and specific mutations (mts) assessed by limited targeted profiling (LTP) with PD-L1 tumour expression (exp) in resected non-small cell lung carcinoma (NSCLC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11587-11587 ◽  
Author(s):  
Jane Sze Yin Sui ◽  
MinYuen Teo ◽  
Sinead Toomey ◽  
Shereen Rafee ◽  
Julia McFadden ◽  
...  
Keyword(s):  
Cancer Genomics ◽  
Small Cell Lung Carcinoma ◽  
Objective Response ◽  
Inverse Correlation ◽  
Cell Lung Carcinoma ◽  
Resected Nsclc ◽  
Nsclc Patients ◽  
The Impact ◽  
Clinicopathological Variables ◽  
Membranous Staining

11587 Background: The advent of immunotherapy represents a paradigm shift in the treatment of NSCLC compared to conventional chemotherapy. Recent studies have shown higher mts burden assessed by exome sequencing are associated with improved objective response and clinical benefit. We performed this study to evaluate the impact of ML assessment by LTP, correlating with PD-L1 exp and clinicopathological variables in resected NSCLC. Methods: NSCLC patients(pts) who underwent curative resection between 1998 and 2006 at our institution were included. PD-L1 status was assessed using Ventana SP124 antibody on archival FFPE surgical tumour specimens cores. PD-L1 was scored positive if membranous staining was present in >1% of tumour cells aggregated across the replicate cores to address heterogeneity. In collaboration with the Lung Cancer Genomics Ireland Study a targeted panel of 49 genes were assessed by Sequenom MassArray including genes in MAPK and PI3K pathways. Clinical data was obtained from hospital electronic database. Results: Ninety-one pts were included, of which 51 (56.0%) were males, with a median age of 65 years (range: 42 – 82). 51.6%, n=47 with squamous histological subtypes, 46.2%, n=42 were ex-smoker and 49.5%, n=45 had Stage I disease. 23.1%, n=21 had PD-L1 positivity. 149 mts were identified of which, 32(21.5%) with PHLPP2, 31(20.9%) with PIK3R1 and 21(14.1%) with TP53. The presence of PI3K and TP53 mts are associated with positive PD-L1 status (see table). An inverse correlation of PD-L1 positivity with ML of (1 vs 2 vs 3: 53.8% vs 30.8% vs 15.4%) was noted. Conclusions: We did not identify higher PD-L1 exp with higher ML assessed by a LTP widely used in clincial practice. However, positive PD-L1 exp was correlated with PIK3R1 and TP53 mts , warranting further investigation as potential modulators or surrogates of positve PD-L1 expression. [Table: see text]

Overall survival results for durvalumab and savolitinib in metastatic papillary renal cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 619-619 ◽  
Author(s):  
Cristina Suarez Rodriguez ◽  
James M. G. Larkin ◽  
Poulam Patel ◽  
Begona Pérez Valderrama ◽  
Alejo Rodriguez-Vida ◽  
...  
Keyword(s):  
Overall Survival ◽  
Renal Cancer ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Treatment Naïve ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3 ◽  
Treatment Safety

619 Background: There is a strong rationale for investigating MET and PD-L1 inhibition in metastatic papillary renal cancer (PRC). We previously reported response rates (RR) and progression free survival (PFS) for savolitinib (MET inhibitor) and durvalumab (PD-L1 inhibitor) together. Here we report overall survival (OS) data available 12 months after the last patient was enrolled. Methods: This single arm phase I/II trial explores durvalumab (1500mg Q4W) and savolitinib (600mg OD) together in PRC, with a 4wk savolitinib run in. Treatment naïve or previously treated patients with metastatic PRC were included. Confirmed RR (RECIST v1.1), PFS, tolerability (CTCAE v4.03) and overall survival (OS) were analysed. MET and PD-L1 biomarkers were explored (NCT02819596). Results: 42 patients were enrolled with 41 receiving at least one dose of study treatment. Safety and efficacy analyses were performed on these 41 patients. The median follow up was 14.3 months. IMDC good, intermediate and poor risk disease occurred in 29%, 63%, and 7% of patients respectively. Overall confirmed RR was 27% while median PFS was 4.9 months (95% CI: 2.5 – 12.0 months). Median OS was 12.3 months (95% CI: 5.8 – 21.3 months). Confirmed RR and median OS in the previously untreated cohort (N=27) were 33% and 12.3 months (95% CI: 4.7 – not reached (NR) months) respectively. Treatment related Grade 3/4 toxicity occurred in 34% of patients. No new safety signals were seen. PD-L1 and MET expression were not associated with higher RR (25% and 40% respectively) or longer OS. Conclusions: The combination of savolitinib and durvalumab has clinical activity in PRC and outcomes were not enhanced in biomarker positive cancers. Clinical trial information: NCT02819596.

scholarly journals Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib

Blood ◽  
2015 ◽  
Vol 125 (16) ◽  
pp. 2497-2506 ◽  
Author(s):  
John C. Byrd ◽  
Richard R. Furman ◽  
Steven E. Coutre ◽  
Jan A. Burger ◽  
Kristie A. Blum ◽  
...  
Keyword(s):  
Adverse Events ◽  
Single Agent ◽  
Extended Treatment ◽  
Key Points ◽  
Treatment Naïve ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3 ◽  
Over Time

Key Points Three-year follow-up of ibrutinib in CLL demonstrated continued activity with durable responses that improve in quality with extended treatment. Toxicity diminished over time with respect to grade ≥3 cytopenias, fatigue, infections, and adverse events leading to discontinuation.

Phase II study of amrubicin (AMR) in patients (pts) with non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy: WJTOG0401

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8059-8059
Author(s):  
H. Hayashi ◽  
H. Kaneda ◽  
I. Okamoto ◽  
M. Miyazaki ◽  
S. Kudoh ◽  
...  
Keyword(s):  
Stable Disease ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Objective Response ◽  
Activity Level ◽  
Clinical Activity ◽  
Significant Activity ◽  
Platinum Based Chemotherapy ◽  
Previously Treated ◽  
Grade 3

8059 Background: AMR is a totally synthetic 9-aminoanthracycline and a novel topoisomerase II inhibitor. AMR has shown promising clinical activity for advanced NSCLC as well as SCLC. This trial was conducted to evaluate the efficacy and safety of AMR for pts with NSCLC previously treated with platinum-based chemotherapy. Methods: Eligible pts had a performance status 0 to 1, previous treatment with one platinum-based chemotherapy for advanced NSCLC, and adequate organ function. Pts received AMR 40 mg/m2 intravenously on days 1–3 every 3 weeks. The primary endpoint was the objective response rate, which determined the sample size based on an optimal two-stage design. With the target activity level of 18% and the lowest response rate of interest set at 5%, 60 eligible patients were required with a 90% power to accept the hypothesis and a 5% significance level to reject the hypothesis. Results: Sixty-one pts (median age, 63 years; range 51–74 years) were enrolled. The median treatment cycles were 2 (range, 1–15). No complete responses and 7 partial responses were observed, giving an overall response rate of 11.5% (95% CI, 4.7–22.2%). Twenty patients (32.8%) had stable disease and 34 patients (55.7%) had progressive disease as the best response. The overall disease control rate (complete response + partial response + stable disease) was thus 44.3% (95% CI, 31.5–57.6%). The median overall survival and 1-year survival rate were 8.5 months and 32.0%, respectively. Grade 3/4 hematological toxicities were neutropenia (82%), anemia (27.9%) and thrombocytopenia (24.6%). Grade 3/4 non-hematological toxicities were anorexia (9.8%), febrile neutropenia (29.5%) and pneumonitis (1.6%). No treatment-related death and cardiac toxicity were observed. Conclusions: AMR exhibits significant activity with manageable toxicities as second-line therapy for advanced NSCLC. [Table: see text]

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