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8503
Background: Small pilot studies (e.g., N Engl J Med. 2018;378:1976) have shown that preoperative immune checkpoint inhibitor therapy may be of benefit in early-stage NSCLC. This ...large multicenter trial assesses the benefit of neoadjuvant treatment with atezolizumab (atezo; NCT02927301). Methods: Patients (pts) with stages IB to selected IIIB resectable NSCLC receive 2 cycles of atezo 1200 mg (days 1, 22) then undergo resection (day 40 ± 10). Primary tumor +/- node biopsies and blood samples are obtained before atezo and at surgery for biomarker studies. The primary endpoint is major pathological response (MPR), defined as ≤ 10% viable tumor cells in the resection specimen. Secondary endpoints include safety and correlation of response with PD-L1 expression, tumor mutation burden (TMB) and gene expression signatures. Results: For this interim efficacy analysis (5 Sep 2018 data cut), we report on the first 101 of 180 planned pts: 47 males, median age, 64 y; all ECOG PS 0-1; 23 current and 68 former smokers; 66 non-squamous NSCLC; clinical stages IB/IIA/IIB/IIIA/IIIB n = 11/16/28/39/7. There were 2 treatment-unrelated Gr 5 AEs (cardiac death post surgical resection; death due to disease progression), 29 Gr 3-4 AEs (6 6% treatment related). 90 pts had surgery. Excluding 8 pts who had driver mutations (7 EGFR, 1 ALK, no MPR), MPR rate was 15/82 (18%, 95% CI 11%-28%), 4 pts had pathological complete response (pCR). By RECIST, 6/82 pts had PR, 72 had SD and 4 had PD. Two of 26 (8%) PD-L1− (TC0 and IC0, clone SP142) and 10 of 35 (29%) PD-L1+ had MPR ( P= 0.055). Five of 44 (11%) TPS < 50 (PD-L1 clone 22C3) and 7 of 20 (35%) TPS > 50 had MPR ( P= 0.040). Exome sequencing data was available for 47/101 pts. Median TMB was 10.4 (range, 1.5-46.5) mutations per Mb and was not different in those with MPR compared with those without MPR. Further analysis of TMB, mutation signatures, and gene expression profiling is ongoing. Conclusions: Atezo in the neoadjuvant setting was well tolerated, and pCR and MPR rates are encouraging in this large multicenter trial. Efficacy interim analysis passed its futility boundary, and study enrollment continues. Safety, efficacy results and ongoing correlative analyses will be presented. Clinical trial information: NCT02927301.
Motexafin gadolinium (MGd) is a putative radiation enhancer initially evaluated in patients with brain metastases. This Phase I trial studied the safety and tolerability of a 2-6-week course (10-22 ...doses) of MGd with radiotherapy for glioblastoma multiforme.
A total of 33 glioblastoma multiforme patients received one of seven MGd regimens starting at 10 doses of 4 mg/kg/d MGd and escalating to 22 doses of 5.3 mg/kg/d MGd (5 or 10 daily doses then three times per week). The National Cancer Institute Cancer Therapy Evaluation Program toxicity and stopping rules were applied.
The maximal tolerated dose was 5.0 mg/kg/d MGd (5 d/wk for 2 weeks, then three times per week) for 22 doses. The dose-limiting toxicity was reversible transaminase elevation. Adverse reactions included rash/pruritus (45%), chills/fever (30%), and self-limiting vesiculobullous rash of the thumb and fingers (42%). The median survival of 17.6 months prompted a case-matched analysis. In the case-matched analysis, the MGd patients had a median survival of 16.1 months (n = 31) compared with the matched Radiation Therapy Oncology Group database patients with a median survival of 11.8 months (hazard ratio, 0.43; 95% confidence interval, 0.20-0.94).
The maximal tolerated dose of MGd with radiotherapy for glioblastoma multiforme in this study was 5 mg/kg/d for 22 doses (daily for 2 weeks, then three times weekly). The baseline survival calculations suggest progression to Phase II trials is appropriate, with the addition of MGd to radiotherapy with concurrent and adjuvant temozolomide.
Background Dysregulation of the hepatocyte growth factor (HGF)/MET pathway is associated with poor prognosis, more aggressive biological characteristics of the tumor, and shortened survival in ...patients with metastatic colorectal cancer (mCRC). Onartuzumab (MetMAb) is a recombinant humanized monovalent monoclonal antibody directed against MET. We present the treatment rationale and protocol for an ongoing randomized multicenter placebo-controlled phase II study designed to evaluate the efficacy and safety of MetMAb combined with bevacizumab and mFOLFOX-6 (5-fluoruracil, leucovorin, and oxaliplatin). Patients and Methods Eligible patients with previously untreated mCRC are randomized 1:1 to either mFOLFOX-6 combined with bevacizumab and placebo followed by 5-fluorouracil/leucovorin plus bevacizumab and placebo or mFOLFOX6, bevacizumab plus MetMAb followed by 5 FU/LV, bevacizumab, and MetMAb. The primary end point of this study is progression-free survival (PFS) in the intent-to-treat (ITT) population. Secondary end points include overall survival (OS), objective response rate, and safety. Subanalyses will be performed to evaluate the effect of MET receptor expression on study primary and secondary end points. Correlative studies will be performed on tissue- and blood-derived biomarkers related to both HGF/MET signaling and other associated pathway markers.
Purpose Bevacizumab regimens are approved for the treatment of recurrent glioblastoma in many countries. Aberrant mesenchymal-epithelial transition factor (MET) expression has been reported in ...glioblastoma and may contribute to bevacizumab resistance. The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. Methods At first recurrence after chemoradiation, bevacizumab-naïve patients with glioblastoma were randomly assigned 1:1 to receive Ona (15 mg/kg, once every 3 weeks) + Bev (15 mg/kg, once every 3 weeks) or Pla + Bev until disease progression. The primary end point was progression-free survival by response assessment in neuro-oncology criteria. Secondary end points were overall survival, objective response rate, duration of response, and safety. Exploratory biomarker analyses correlated efficacy with expression levels of MET ligand hepatocyte growth factor, O
-methylguanine-DNA methyltransferase promoter methylation, and glioblastoma subtype. Results Among 129 patients enrolled (Ona + Bev, n = 64; Pla + Bev, n = 65), baseline characteristics were balanced. The median progression-free survival was 3.9 months for Ona + Bev versus 2.9 months for Pla + Bev (hazard ratio, 1.06; 95% CI, 0.72 to 1.56; P = .7444). The median overall survival was 8.8 months for Ona + Bev and 12.6 months for Pla + Bev (hazard ratio, 1.45; 95% CI, 0.88 to 2.37; P = .1389). Grade ≥ 3 adverse events were reported in 38.5% of patients who received Ona + Bev and 35.9% of patients who received Pla + Bev. Exploratory biomarker analyses suggested that patients with high expression of hepatocyte growth factor or unmethylated O
-methylguanine-DNA methyltransferase may benefit from Ona + Bev. Conclusion There was no evidence of further clinical benefit with the addition of onartuzumab to bevacizumab compared with bevacizumab plus placebo in unselected patients with recurrent glioblastoma in this phase II study; however, further investigation into biomarker subgroups is warranted.
1076
Background: SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG is approved for pts with mTNBC ...who received ≥2 prior chemotherapies (> 1 in the metastatic setting). The relationships between exposure of SG, free SN-38, and total antibody (tAB) following SG administration and its efficacy and safety outcomes were evaluated in pts with mTNBC. Methods: Available exposure efficacy and safety outcomes from the mTNBC cohort of the phase 1/2 IMMU-132-01 study (relapsed/refractory pts; n = 24) and mTNBC pts from the phase 3 ASCENT study who had received ≥2 prior therapies (> 1 in the metastatic setting; n = 253) were analyzed. Pts in IMMU-132-01 received 8 or 10 mg/kg SG and pts in ASCENT received 10 mg/kg SG on d1 and d8, of every 21d cycle. Effect of exposure on CR, ORR and the evaluated adverse events (AEs) of vomiting, diarrhea, hypersensitivity reactions, nausea, and neutropenia were analyzed using logistic (CR, ORR) or ordinal logistic (AE) regression models while OS, PFS, time to first dose reduction and time to first dose delay were analyzed using Cox PH models. Several exposure metrics related to the PK of SG, free SN-38, and tAB were evaluated as predictors of SG efficacy and safety and the most statistically significant exposure metric was retained in the model; effect of other covariates was characterized within the modeling framework. Results: Higher values of the average exposure over the treatment duration (CAVG) for SG (CAVG
SG
) were significantly associated with an increase in the probability of CR and ORR and higher CAVG values for tAB (CAVG
tAB
)
were significantly associated with longer OS and PFS. The probability of Grade ≥1 evaluated AEs, the risk of dose reductions and dose delays were found to increase significantly with increasing CAVG
SG
. Neutropenia was the only AE where the effect of exposure was significantly associated with the probability of Grade ≥3 evaluated AEs. No statistically significant associations between exposure and the probability of Grade 4 AEs were observed for any of the evaluated endpoints. The developed models were used to estimate the efficacy and safety outcomes for the 8 mg/kg vs 10 mg/kg SG dose levels and the results indicated a more favorable risk/benefit profile for the 10 mg/kg dose level driven by the higher estimated efficacy. Baseline Trop-2 expression level was not statistically correlated with magnitude of clinical response based on the limited available Trop-2 data. Conclusions: Exposure-response relationships were observed for all evaluated efficacy and safety endpoints for SG in patients with mTNBC, and the higher efficacy (as assessed by CR, ORR, OS and PFS) achieved with the exposures associated with the 10 mg/kg SG dose regimen and its manageable safety profile support the appropriateness of the approved regimen of SG. Clinical trial information: NCT02574455, NCT01631552.
Chronic lymphocytic leukemia (CLL) cells are susceptible to oxidative stress. The expanded porphyrin, motexafin gadolinium (MGd), reacts with intracellular reducing metabolites and protein thiols to ...generate reactive oxygen species (ROS). A phase II trial administered MGd 5 mg/kg/day IV for 5 days every 3 weeks until disease progression to patients with previously treated CLL and small lymphocytic lymphoma. Thirteen patients (median age 66 years) with a median of four prior therapies (range 2-9) were enrolled. Modest anti-tumor activity was seen in three patients, with improvement in lymphocytosis, lymphadenopathy and/or splenomegaly, but no patient achieved a partial or complete response by NCI 96 criteria. Flow cytometry confirmed tumor uptake of MGd. Serial increase in AKT phosphorylation in patient samples following MGd treatment was not observed, suggesting intracellular generation of ROS was not optimal. Therefore, this schedule of administration achieved MGd uptake into primary tumor cells in vivo, but clinical activity was modest.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
1071
Background: Treatment goals for pts with metastatic breast cancer include extended survival and improved quality of life (QoL). SG is an antibody-drug conjugate composed of an anti–Trop-2 ...antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG received FDA approval for pts with mTNBC who received ≥2 prior chemotherapies (at least 1 in the metastatic setting). In the pivotal phase 3 ASCENT study (NCT02574455), SG demonstrated a significant survival benefit over single-agent chemotherapy TPC in the primary analysis population of pts with second line or greater (2L+) mTNBC without known brain metastases at baseline (Bardia A et al. NEJM 2021) and QoL (Loibl S. et al. ESMO 2021). With additional follow up, we present the final data on efficacy, including overall survival (OS), safety, and QoL. Methods: Pts with mTNBC refractory or relapsing after ≥2 prior chemotherapies with at least 1 in the metastatic setting were randomized 1:1 to receive SG (10 mg/kg IV on days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. Primary endpoint was progression-free survival (PFS) per RECIST 1.1 by independent review in pts without known brain metastases at baseline. Key secondary endpoints included OS, safety, and health-related QoL. Safety was analyzed in pts who received ≥1 dose of study drug. Results: Of 529 pts enrolled, 468 did not have known brain metastases at baseline (median age: 54 y range, 27-82; median prior lines: 4 range, 2-17). As of Feb 25, 2021 (final database lock), SG (n = 235) vs TPC (n = 233) significantly improved median PFS (5.6 vs 1.7 mo; HR: 0.39; P< 0.0001) and median OS (12.1 vs 6.7 mo; HR: 0.48; P< 0.0001). The OS rate at 24 months was 22.4% (95% CI, 16.8-28.5) in the SG arm and 5.2% (95% CI, 2.5-9.4) in the TPC arm. In the safety population (n = 482), key treatment-related grade ≥3 adverse events with SG (n = 258) vs TPC (n = 224) were diarrhea (11% vs 0.4%), neutropenia (52% vs 33%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%). There was no grade ≥3 neuropathy and 1 case of grade 3 interstitial lung disease reported with SG. No patient experienced a treatment-related death with SG, and there was 1 treatment-related death with TPC due to neutropenic sepsis. Treatment discontinuations due to AEs were ≤3% in both arms. SG arm showed clinically meaningful and statistically significant improvements than the TPC arm in scores for all five primary focus health-related QoL domains. Conclusions: The analysis based on the final database lock of ASCENT confirms the superior survival outcomes of SG over single-agent chemotherapy, with a manageable safety profile and improvement in QoL for pts with mTNBC in the 2L+ setting. These findings reinforce SG as an effective treatment option for this pt population. Clinical trial information: NCT02574455.
Motexafin gadolinium is a novel antineoplastic drug that disrupts cancer cell antioxidant systems, thus contributing to cellular death. In patients with lung cancer, motexafin gadolinium has been ...shown to increase the time to neurologic progression when given in combination with whole-brain radiotherapy in randomized phase III studies. Preclinical data suggest that this drug might also enhance the antineoplastic effects of chemotherapy.
In this one-arm, open label, phase I, dose-escalation study, we administered docetaxel (75 mg/m2), cisplatin (75 mg/m2), and motexafin gadolinium every 3 weeks to patients with metastatic non-small cell lung cancer. Twenty-one patients were treated at one of four motexafin dose levels.
The maximal tolerated motexafin dose was 10 mg/kg on day 1 of a 3-week cycle. Dose-limiting toxicities consisted of febrile neutropenia, hypertension, myocardial ischemia, and pneumonitis/pulmonary infiltrates. Other common grade 3–4 adverse events across all cohorts that did not appear to be exacerbated by motexafin gadolinium included granulocytopenia, fatigue, dehydration, nausea, and vomiting. Two episodes of myocardial ischemia and one sudden death of unknown cause were observed. Response rates were partial response (10%), stable disease (60%), and disease progression (30%).
The regimen studied was tolerable and showed activity in patients with metastatic non-small cell lung cancer. The recommended doses for future phase II trials are motexafin gadolinium 10 mg/kg, docetaxel 75 mg/m2, and cisplatin 75 mg/m2 intravenously on day 1 every 3 weeks. Caution is advised in patients with a history of cardiovascular disease.
The purpose of this study was to determine clinical variables affecting motexafin gadolinium (MGd) pharmacokinetics. Motexafin gadolinium (4–5.3 mg/kg/d) was administered intravenously for 2 to 6.5 ...weeks. Plasma samples from 3 clinical trials were analyzed for MGd using liquid chromatography/mass spectroscopy. The pooled data were analyzed using population pharmacokinetic (POP‐PK) methods. The POP‐PK model included 243 patients (1575 samples). Clearance (CL) was 14% lower in women, but weight‐normalized clearance was only 5% lower in women. Clearance decreased with increasing alkaline phosphatase, increasing age, and decreasing hemoglobin. Administration of phenytoin increased CL by approximately 30%. Central compartment volume (V1) was 21% lower in women and increased with increasing serum creatinine. For all covariates, except sex and phenytoin, the predicted change in CL or V1 (5th and 95th percentiles) varied ≤13% from the population mean CL or V1 estimate. It was concluded that a 3‐compartment, open, POP‐PK model predicts small but significant effects of age, sex, alkaline phosphatase, hemoglobin, serum creatinine, and phenytoin on MGd pharmacokinetics.
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3064
Background: Immune checkpoint blockade in non-small cell lung cancer (NSCLC) may be enhanced when combined with radiation therapy. Atezolizumab (atezo) is a humanized and Fc ...receptor modified monoclonal antibody that blocks programmed death-ligand-1 (PD-L1) interacting with PD-1 or B7.1 sparing PD-L2, which may result in less pulmonary toxicity. We report the early safety data of combining atezo added sequentially after standard concomitant chemoradiation (CRT) for locally advanced NSCLC (LA-NSCLC). Methods: This is a phase II study in LA-NSCLC assessing the safety and feasibility of adding atezo to CRT in two parts: I) sequentially (N = 10) with CP after completing CRT, or II) concurrently (N = 30) with CRT followed by consolidation atezo with CP. We report on the early toxicity results from part I of the trial. Atezo was given at 1200 mg IV Q3 weeks with consolidation CP for 2 cycles after CRT followed by atezo monotherapy for up to one year. Radiation dose at 60-66 Gy in 30-33 fractions was combined with weekly low dose CP, followed by 2 cycles of full dose CP. Dose limiting toxicities were defined as any adverse events (AEs) ≥ grade 3 within 15 weeks of start of therapy or any immune-related AEs during atezo treatment. Results: From January to December 2016, 10 evaluable patients were enrolled. Seven patients have received consolidation atezo ranging from 1 to 14 doses, with 3 yet to receive atezo after completing CRT. Three patients reported potential immune-related AEs. One patient developed grade 3 arthralgia, and another developed grade 2 radiation-induced pneumonitis, which resolved with steroids. A third patient who experienced grade 3 dyspnea due to COPD exacerbation after 1 dose of atezo discontinued additional therapy. Of the 7 patients who have received atezo, 2 patients developed progression of disease after 6 and 8 doses of atezo. Conclusions: Atezo consolidation with 2 cycles of CP after CRT appears to be feasible and well tolerated with manageable toxicities. Additional data from part I will be reported. Conditions for proceeding after part I are met and part II of the study which adds atezo to CRT followed by atezo-CP consolidation is open for accrual. Clinical trial information: NCT02525757.
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