Purpose
This study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK ...and/or AKT inhibition.
Methods
This was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or
BRAF
-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD.
Results
Adverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses).
Conclusions
Continuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Triple-negative breast cancer (TNBC) is an aggressive malignancy for which cytotoxic chemotherapy remains the backbone of treatment. Trilaciclib is an intravenous cyclin-dependent kinase 4/6 ...inhibitor that induces transient cell cycle arrest of hematopoietic stem and progenitor cells and immune cells during chemotherapy exposure, protecting them from chemotherapy-induced damage and enhancing immune activity. Administration of trilaciclib prior to gemcitabine plus carboplatin (GCb) significantly improved overall survival (OS) compared with GCb alone in an open-label phase II trial in patients with metastatic TNBC, potentially through protection and direct activation of immune function. The randomized, double-blind, placebo-controlled, phase III PRESERVE 2 trial will evaluate the efficacy and safety of trilaciclib administered prior to GCb in patients with locally advanced unresectable or metastatic TNBC.
: NCT04799249 (ClinicalTrials.gov).
PI3K/AKT signaling pathway is activated in breast cancer and associated with cell survival. We explored the prevalence of PI3K pathway alterations and co-expression with other markers in breast ...cancer subtypes.
Samples of non-matched primary and metastatic breast cancer submitted to a CLIA-certified genomics laboratory were molecularly profiled to identify pathogenic or presumed pathogenic mutations in the
pathway using next generation sequencing. Cases with loss of PTEN by IHC were also included. The frequency of co-alterations was examined, including DNA damage response pathways and markers of response to immuno-oncology agents.
Of 4,895 tumors profiled, 3,558 (72.7%) had at least one alteration in the
pathway: 1,472 (30.1%) harbored a
mutation, 174 (3.6%) an
mutation, 2,682 (54.8%) had PTEN alterations (
mutation in 7.0% and/or PTEN loss by IHC in 51.4% of cases), 81 (1.7%) harbored a
mutation, and 4 (0.08%) a
mutation. Most of the cohort consisted of metastatic sites (
= 2974, 60.8%), with
mutation frequency increased in metastatic (32.1%) compared to primary sites (26.9%),
< 0.001. Other
mutations were identified in 388 (7.9%) specimens, classified as "off-label," as they were not included in the FDA-approved companion test for
mutations. Notable co-alterations included increased PD-L1 expression and high tumor mutational burden in
mutated cohorts. Novel concurrent mutations were identified including
mutations.
Findings from this cohort support further exploration of the clinical benefit of PI3K inhibitors for "off-label"
mutations and combination strategies with potential clinical benefit for patients with breast cancer.
Purpose
Estrogen receptor 1
(
ESR1
) mutations and fusions typically arise in patients with hormone receptor-positive breast cancer after aromatase inhibitor therapy, whereby ESR1 is constitutively ...activated in a ligand-independent manner. These variants can impact treatment response. Herein, we characterize
ESR1
variants among molecularly profiled advanced breast cancers.
Methods
DNA next-generation sequencing (592-gene panel) data from 9860 breast cancer samples were retrospectively reviewed. Gene fusions were detected using the ArcherDx fusion assay or whole transcriptome sequencing (
n
= 344 and
n
= 4305, respectively). Statistical analyses included Chi-square and Fisher’s exact tests.
Results
An
ESR1
ligand-binding domain (LBD) mutation was detected in 8.6% of tumors evaluated and a pathogenic
ESR1
fusion was detected in 1.6%. Most
ESR1
LBD mutations/fusions were from estrogen receptor (ER)-positive samples (20.1% and 4.9%, respectively). The most common
ESR1
LBD mutations included D538G (3.3%), Y537S (2.3%), and E380Q (1.1%) mutations. Among biopsy sites,
ESR1
LBD mutations were most observed in liver metastases. Pathogenic
ESR1
fusions were identified in 76 samples (1.6%) with 40 unique fusion partners. Evaluating co-alterations,
ESR1
variant (mutation/fusion) samples more frequently expressed androgen receptor (78.0% vs 58.6,
P
< 0.0001) and less frequently immune checkpoint proteins than
ESR1
wild-type (PD-1 20.0% vs 53.4,
P
< 0.05; immune cell PD-L1 10.0% vs 30.2,
P
< 0.0001).
Conclusion
We have described one of the largest series of
ESR1
fusions reported.
ESR1
LBD mutations were commonly identified in ER-positive disease. Limited data exists regarding the clinical impact of
ESR1
fusions, which could be an area for future therapeutic exploration.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The poly(ADP-ribose) polymerases (PARPs) 1 and 2 are DNA-binding enzymes that play a critical role in the repair of DNA. The use of PARP inhibitors is a rational therapeutic approach to selectively ...killing a subset of cancer cells with deficiencies in DNA repair pathways. PARP inhibitors that have undergone clinical investigation in the treatment of breast cancer include olaparib, talazoparib, veliparib, niraparib, and rucaparib. The antitumor activity of PARP inhibitors as single agents has been demonstrated in BRCA-associated metastatic breast cancer. In 2018, olaparib became the first oral PARP inhibitor to receive approval in the United States for the treatment of advanced BRCA-mutated breast cancer, an approval that represents a major change in the treatment paradigm for this subtype of breast cancer. PARP inhibition plus chemotherapy and PARP inhibition plus immunotherapy are novel approaches undergoing extensive study in breast cancer. This review focuses on the clinical development of PARP inhibitors administered singly or in combination with other agents for early-stage and metastatic BRCA-mutated breast cancer.
Purpose
Given the evidence that coordinate inhibition of AKT induces autophagy, we studied the combination of the AKT inhibitor, MK-2206 with hydroxychloroquine (HCQ) in patients with advanced solid ...tumors.
Methods
Patients were treated with weekly MK-2206 (135 mg or 200 mg) plus HCQ (200 mg, 400 mg or 600 mg BID).
Results
Thirty-five patients were enrolled across 5 dose levels. Two DLTs of grade 3 maculo-papular rash were observed at dose level 2 (MK-2206 200 mg weekly plus HCQ at 400 mg BID) and 1 DLT of grade 3 fatigue at dose level 2B (MK-2206 135 mg weekly plus HCQ 600 mg BID). The maximum tolerated dose (MTD) was declared as dose level 2B. The most common adverse events attributed to MK-2206 were hyperglycemia (
N
= 18; 51%), fatigue (
N
= 17; 49%), maculo-papular rash (
N
= 16; 46%), diarrhea (
N
= 12; 34%), anorexia (
N
= 11; 31%), and nausea (
N
= 11; 31%). Patients experiencing adverse events attributed to HCQ were small in number (
N
= 13) and primarily included fatigue (
N
= 5; 14%) and maculo-papular rashes (
N
= 3; 9%). Statistically significant effects on the pharmacokinetic properties of MK-2206 were observed in combination with HCQ. In addition, the plasma concentrations of HCQ in the combination with MK-2206 were significantly higher than the plasma levels of HCQ as monotherapy in prior studies. The best overall response of stable disease was observed in 5/34 (15%) patients.
Conclusion
The combination of MK-2206 and hydroxychloroquine was tolerable, but with substantial number of drug-related AEs and minimal evidence of antitumor activity.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Activation of poly(ADP-ribose) polymerase (PARP) near sites of DNA breaks facilitates recruitment of DNA repair proteins and promotes chromatin relaxation in part through the action of ...chromatin-remodeling enzyme Amplified in Liver Cancer 1 (ALC1). Through proteomic analysis we find that ALC1 interacts after DNA damage with Tripartite Motif-containing 33 (TRIM33), a multifunctional protein implicated in transcriptional regulation, TGF-β signaling, and tumorigenesis. We demonstrate that TRIM33 is dynamically recruited to DNA damage sites in a PARP1- and ALC1-dependent manner. TRIM33-deficient cells show enhanced sensitivity to DNA damage and prolonged retention of ALC1 at sites of DNA breaks. Conversely, overexpression of TRIM33 alleviates the DNA repair defects conferred by ALC1 overexpression. Thus, TRIM33 plays a role in PARP-dependent DNA damage response and regulates ALC1 activity by promoting its timely removal from sites of DNA damage.
Background: PARP activation at sites of DNA breaks leads to recruitment of chromatin remodeling enzymes such as ALC1.
Results: TRIM33 associates with ALC1 after DNA damage and regulates its retention at DNA breaks.
Conclusion: TRIM33 has a role in the PARP-dependent DNA damage response pathway.
Significance: The role of TRIM33 in the DNA repair may contribute to its known tumor suppressor function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
The extent of residual disease after neoadjuvant chemotherapy (NAC) can be quantified by the Residual Cancer Burden (RCB), a prognostic tool used to estimate survival outcomes in breast ...cancer. This study investigated the association between RCB and locoregional recurrence (LRR).
Methods
The study reviewed 532 women with breast cancer who underwent NAC between 2010 and 2016. Relapse in the ipsilateral breast, skin/subcutis at the surgical site, chest wall, pectoralis, or regional lymph nodes defined an LRR. The LRR cumulative incidence (LRCI) was estimated using the Fine and Gray competing-risks model, with death and distant recurrence defined as competing events. The association of LRCI with prognostic variables was evaluated.
Results
Overall, 5.5% of the patients experienced an LRR after a median follow-up period of 65 months. The 5-year LRCI rates by RCB were as follows: RCB-0 (0.9%), RCB-1 (3.2%), RCB-2 (6.0%), and RCB-3 (12.9%). In the univariable analysis, LRCI varied significantly by RCB (
p
= 0.010). The multivariable analysis showed a significant association of LRCI with increasing RCB, and the patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) phenotype were at lower risk for LRR than those with HER2+ and triple-negative cancers (
p
< 0.032). The patients with RCB-3 were at a higher risk for local relapse than those with RCB-0 (hazard ratio, 13.78; confidence interval, 2.25–84.45;
p
= 0.04). Type of operation (
p
= 0.04) and use of adjuvant radiation (
p
= 0.046) were statistically significant in the multivariable model.
Conclusions
The study results demonstrate a significant association between LRCI and increasing RCB, although distant recurrence is a substantial driver of disease outcomes. Future prospective studies should examine the role of RCB in clinical decisions regarding indications for adjuvant therapy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
To evaluate the effect of renal impairment on eribulin mesylate pharmacokinetics following a single dose in adults with advanced solid tumors.
Methods
Patients were grouped by renal function: ...moderate impairment (creatinine clearance CrCl 30–50 mL/min), severe impairment (CrCl 15–29 mL/min), or normal (CrCl ≥80 mL/min). During each 21-day cycle, eribulin mesylate doses (days 1 and 8) were administered intravenously: moderate, 1.1 mg/m
2
(except cycle 1 day 1, 1.4 mg/m
2
); severe, 0.7 mg/m
2
; normal, 1.4 mg/m
2
.
Results
Nineteen patients were enrolled (normal,
n
= 6; moderate,
n
= 7; severe,
n
= 6). Renal impairment was associated with an increased mean dose-normalized area under the concentration–time curve (ratios for moderate/normal and severe/normal: 1.49; 90 % confidence interval CI 0.9, 2.45). CrCl and renal function correlated positively, with a numerically small slope (0.0184; 90 % CI −0.00254, 0.0394). A simulated dose reduction to eribulin 1.1 mg/m
2
in patients with moderate or severe renal impairment achieved the same exposure as 1.4 mg/m
2
in those with normal renal function. All groups had similar toxicity profiles, with no unexpected adverse events.
Conclusions
Renal impairment decreased eribulin clearance and increased exposure. Pharmacokinetic evaluation supports an eribulin dose reduction to 1.1 mg/m
2
in patients with moderate or severe renal impairment.
ClinicalTrials.gov Identifier
NCT01418677.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
The metabolism of pazopanib is primarily mediated by CYP3A4. The solubility of pazopanib is pH-dependent, and an elevated gastric pH may decrease its bioavailability. This study evaluated the ...effect of a potent CYP3A4 inhibitor, ketoconazole, and the proton pump inhibitor esomeprazole on the pharmacokinetics and safety of pazopanib and its metabolites.
Methods
In Arm A, patients received pazopanib 400 mg alone once daily for 7 days followed by pazopanib 400 mg plus ketoconazole 400 mg once daily for 5 days. In Arm B, patients received pazopanib 800 mg once daily for 7 days, followed by pazopanib 800 mg plus esomeprazole 40 mg once daily for 5 days, and then pazopanib alone on the last day.
Results
Arm A enrolled 21 patients. In the presence of ketoconazole, mean area under the plasma concentration–time curve 24 h post-dose (AUC
(0–24)
) and mean maximum observed concentration (
C
max
) of pazopanib increased by 66 and 45 %, respectively; mean AUC
(0–24)
and
C
max
for pazopanib metabolites were lower or remained unchanged. Arm B enrolled 13 patients. In the presence of esomeprazole, mean pazopanib AUC
(0–24)
and
C
max
decreased by 40 and 42 %, respectively; mean values of those parameters for metabolites of pazopanib also decreased.
Conclusions
Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided. If coadministration is necessary, pazopanib should be reduced to 400 mg. Concomitant use of pazopanib and proton pump inhibitors should also be avoided. Alternative dosing regimens that do not increase gastric pH at the time of pazopanib dosing should be considered.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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