Standard therapy for metastatic, hormone-sensitive prostate cancer is androgen-deprivation therapy, usually with docetaxel. A large, multinational, phase 3 trial assessed the addition of the ...androgen-receptor blocker darolutamide to standard therapy. At 4 years, survival was higher with darolutamide than with placebo (62.7% vs. 50.4%), with no major differences in the frequency of adverse events.
Summary Background Until now, only imatinib and sunitinib have proven clinical benefit in patients with gastrointestinal stromal tumours (GIST), but almost all metastatic GIST eventually develop ...resistance to these agents, resulting in fatal disease progression. We aimed to assess efficacy and safety of regorafenib in patients with metastatic or unresectable GIST progressing after failure of at least imatinib and sunitinib. Methods We did this phase 3 trial at 57 hospitals in 17 countries. Patients with histologically confirmed, metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib were randomised in a 2:1 ratio (by computer-generated randomisation list and interactive voice response system; preallocated block design (block size 12); stratified by treatment line and geographical region) to receive either oral regorafenib 160 mg daily or placebo, plus best supportive care in both groups, for the first 3 weeks of each 4 week cycle. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was progression-free survival (PFS). At disease progression, patients assigned placebo could crossover to open-label regorafenib. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01271712. Results From Jan 4, to Aug 18, 2011, 240 patients were screened and 199 were randomised to receive regorafenib (n=133) or matching placebo (n=66). Data cutoff was Jan 26, 2012. Median PFS per independent blinded central review was 4·8 months (IQR 1·4–9·2) for regorafenib and 0·9 months (0·9–1·8) for placebo (hazard ratio HR 0·27, 95% CI 0·19–0·39; p<0·0001). After progression, 56 patients (85%) assigned placebo crossed over to regorafenib. Drug-related adverse events were reported in 130 (98%) patients assigned regorafenib and 45 (68%) patients assigned placebo. The most common regorafenib-related adverse events of grade 3 or higher were hypertension (31 of 132, 23%), hand-foot skin reaction (26 of 132, 20%), and diarrhoea (seven of 132, 5%). Interpretation The results of this study show that oral regorafenib can provide a significant improvement in progression-free survival compared with placebo in patients with metastatic GIST after progression on standard treatments. As far as we are aware, this is the first clinical trial to show benefit from a kinase inhibitor in this highly refractory population of patients. Funding Bayer HealthCare Pharmaceuticals.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background
In the phase 3 GRID trial, regorafenib improved progression-free survival (PFS) independent of
KIT
mutations in exons 9 and 11. In this retrospective, exploratory analysis of the GRID ...trial, we investigated whether a more comprehensive
KIT
mutation analysis could identify mutations that impact treatment outcome with regorafenib and a regorafenib-induced mutation pattern.
Methods
Archived tumor samples, collected at any time prior to enrollment in GRID, were analyzed by Sanger sequencing (
n
= 102) and next-generation sequencing (FoundationONE;
n
= 47). Plasma samples collected at baseline were analyzed by BEAMing (
n
= 163) and SafeSEQ (
n
= 96).
Results
In archived tumor samples, 67% (68/102) had a
KIT
mutation; 61% (62/102) had primary
KIT
mutations (exons 9 and 11) and 12% (12/102) had secondary mutations (exons 13, 14, 17, and 18). At baseline, 81% of samples (78/96) had
KIT
mutations by SafeSEQ, including the M541L polymorphism (sole event in 6 patients). Coexisting mutations in other oncogenes were rare, as were mutations in
PDGFR
,
KRAS
, and
BRAF
. Regorafenib showed PFS benefit across all primary and secondary
KIT
mutational subgroups examined. Available patient-matched samples taken at baseline and end of treatment (
n
= 41; SafeSEQ), revealed heterogeneous
KIT
mutational changes with no specific mutation pattern emerging upon regorafenib treatment.
Conclusion
These data support the results of the GRID trial, and suggest that patients may benefit from regorafenib in the presence of
KIT
mutations and without the selection of particular mutation patterns that confer resistance. The study was not powered to address biomarker-related questions, and the results are exploratory and hypothesis-generating.
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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
Background
The randomized, double-blind, placebo-controlled GRID trial tested the oral multikinase inhibitor regorafenib in 199 patients with advanced gastrointestinal stromal tumors (GIST) following ...failure of at least imatinib and sunitinib, and showed a significant improvement in progression-free survival (PFS) versus placebo hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.19–0.39;
p
< 0.0001.
Methods
A subgroup analysis of Japanese patients in the GRID study was performed to compare the efficacy and safety of oral regorafenib 160 mg once daily with matching placebo, in combination with best supportive care. The primary study endpoint was progression-free survival (PFS); safety was evaluated through the incidence of adverse events (AEs).
Results
Seventeen Japanese patients were randomized to regorafenib (
n
= 12) or placebo (
n
= 5). Patient demographics were consistent with those of the overall study population. PFS was significantly longer with regorafenib than placebo (HR 0.08; 95 % CI 0.02–0.45;
p
= 0.000164). Centrally assessed disease control rates were 58 % and 20 % in the regorafenib and placebo groups, respectively (
p
= 0.080796). Treatment-related adverse events (AEs) were reported in all regorafenib-treated patients and 60 % of placebo recipients; the most frequent AE was hand–foot skin reaction (HFSR) (92 % versus 20 %, respectively).
Conclusion
Regorafenib showed efficacy and a manageable safety profile in Japanese patients with advanced GIST, consistent with the overall GRID study population. AEs, such as HFSR and maculopapular rash, were observed more frequently in Japanese patients. Although dose modification was frequently reported, only one patient with hepatic failure discontinued regorafenib because of AEs.
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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: Apoptosis of circulating CD8+ T cells seen in patients with squamous cell carcinoma of the head and neck SCCHN (Hoffmann
T, et al. Clin Cancer Res 2002;8:2553–62) suggested a possibility of ...lymphocyte imbalance. Therefore, absolute numbers and
percentages of lymphocyte subsets were examined in the peripheral blood of SCCHN patients and controls.
Experimental Design: Venous blood was obtained from 146 patients with SCCHN and 54 normal volunteers. Absolute numbers of CD3+, CD4+, and CD8+
T lymphocytes were determined using fluorobeads in a flow cytometry-based technique. Percentages of T lymphocyte subsets were
also evaluated by flow cytometry. The patients were grouped at the time of blood draw active versus no evidence of disease (NED), type of therapy administered, and the length of follow-up.
Results: Patients with SCCHN had significantly lower absolute numbers of CD3+ CD4+, and CD8+ T cells than normal controls. However,
no differences in the percentages of T-cell subsets between patients and normal controls were observed. Patients with active
disease had significantly lower CD3+ and CD4+ T-cell counts than those with NED. Patients who had NED after surgery and radiotherapy
had the lowest T-cell counts among the NED cohort. Patients who had NED for >2 years did not recover their T-cell counts,
and the T-cell imbalance was evident many years after curative surgery. The tumor-node-metastasis (TNM) stage or site of the
disease was not related to the absolute T-cell count. Patients with recurrent disease at the time of blood draw tended to
have the lowest CD4+ T-cell counts.
Conclusions: Patients with SCCHN have altered lymphocyte homeostasis, which persists for months or years after curative therapies.
Background
Darolutamide, an oral androgen receptor inhibitor, has been approved for treating nonmetastatic castration-resistant prostate cancer (nmCRPC), based on significant improvements in ...metastasis-free survival (MFS) in the ARAMIS clinical trial. Efficacy and safety of darolutamide in Japanese patients are reported here.
Methods
In this randomized, double-blind, placebo-controlled phase III trial, 1509 patients with nmCRPC and prostate-specific antigen (PSA) doubling time ≤ 10 months were randomized 2:1 to darolutamide 600 mg twice daily or matched placebo while continuing androgen deprivation therapy. The primary endpoint was MFS.
Results
In Japan, 95 patients were enrolled and randomized to darolutamide (
n
= 62) or placebo (
n
= 33). At the primary analysis (cut-off date: September 3, 2018), after 20 primary end-point events had occurred, median MFS was not reached with darolutamide vs. 18.2 months with placebo (HR 0.28, 95% CI 0.11–0.70). Median OS was not reached due to limited numbers of events in both groups but favored darolutamide in the Japanese subgroup. Time to pain progression, time to PSA progression, and PSA response also favored darolutamide. Among Japanese patients randomized to darolutamide vs. placebo, incidences of treatment-emergent adverse events (TEAEs) were 85.5 vs. 63.6%, and incidences of treatment discontinuation due to TEAEs were 8.1 vs. 6.1%.
Conclusions
Efficacy outcomes favored darolutamide in Japanese patients with nmCRPC, supporting the clinical benefit of darolutamide in this patient population. Darolutamide was well tolerated; however, due to the small sample size, it is impossible to conclude with certainty whether differences in the safety profile exist between Japanese and overall ARAMIS populations.
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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
Expression of T-cell receptor- or Fc γ receptor III-associated signal-transducing ζ chain is important for the functional integrity of immune cells. We found that
significantly higher proportions of ...circulating CD3 + T cells as well as natural killer cells had low or absent expression of the ζ chain in patients with advanced melanoma than
in normal donors ( P < 0.0005). Decreased ζ expression was always observed in a small subset of circulating CD3 + T cells that were in the process of apoptosis, i.e., bound Annexin V or were terminal deoxynucleotidyl transferase-mediated nick end labeling positive. Up to 80% of T cells in
the peripheral blood of patients with melanoma were Fas + , with the mean percentage of Fas + CD3 + cells significantly higher in patients ( P < 0.004) than normal controls. These Fas + CD3 + T cells were found to preferentially undergo apoptosis. Annexin V binding, the loss of Fas expression from the cell surface
as well as ζ, down-regulation, which are associated with early apoptosis, were detected in a proportion of circulating Fas + CD3 + . In Jurkat cells incubated with agonistic anti-Fas antibody (CH-11), a rapid loss of Fas expression from the cell surface
coincided with Annexin V binding and preceded the loss of ζ chain during early apoptosis. In a subset of Jurkat cells coincubated
with human melanoma cells, Annexin V binding and ζ degradation as well as DNA fragmentation were observed, indicating that
the tumor induced T-cell death. Triggering of death receptors expressed on activated T lymphocytes was accompanied by the
loss of ζ expression. On the other hand, soluble factors secreted by melanoma cells induced down-regulation but no apoptosis
in activated normal T cells. In the circulation of patients with melanoma, apoptosis of immune effector cells may be related
to the state of chronic activation, resulting in the up-regulation of death receptors and increased susceptibility to apoptosis.
Darolutamide, a new antiandrogen agent, was tested in men with recurrence of prostate cancer and a PSA doubling time of less than 10 months. Darolutamide was associated with metastasis-free survival ...of 40.4 months, as compared with 18.4 months for placebo. Toxic effects were similar in the two groups.
Patients with nonmetastatic, castration-resistant prostate cancer with a rapid PSA doubling time were randomly assigned to receive darolutamide or placebo. Overall survival at 3 years was 83% in the ...darolutamide group and 77% in the placebo group, representing a 31% lower risk of death with darolutamide. Toxic effects were similar in the two groups.
For patients with metastatic hormone-sensitive prostate cancer, metastatic burden affects outcome. We examined efficacy and safety from the ARASENS trial for subgroups by disease volume and risk.
...Patients with metastatic hormone-sensitive prostate cancer were randomly assigned to darolutamide or placebo plus androgen-deprivation therapy and docetaxel. High-volume disease was defined as visceral metastases and/or ≥ 4 bone metastases with ≥ 1 beyond the vertebral column/pelvis. High-risk disease was defined as ≥ 2 risk factors: Gleason score ≥ 8, ≥ 3 bone lesions, and presence of measurable visceral metastases.
Of 1,305 patients, 1,005 (77%) had high-volume disease and 912 (70%) had high-risk disease. Darolutamide increased overall survival (OS) versus placebo in patients with high-volume (hazard ratio HR, 0.69; 95% CI, 0.57 to 0.82), high-risk (HR, 0.71; 95% CI, 0.58 to 0.86), and low-risk disease (HR, 0.62; 95% CI, 0.42 to 0.90), and in the smaller low-volume subgroup, the results were also suggestive of survival benefit (HR, 0.68; 95% CI, 0.41 to 1.13). Darolutamide improved clinically relevant secondary end points of time to castration-resistant prostate cancer and subsequent systemic antineoplastic therapy versus placebo in all disease volume and risk subgroups. Adverse events (AEs) were similar between treatment groups across subgroups. Grade 3 or 4 AEs occurred in 64.9% of darolutamide patients versus 64.2% of placebo patients in the high-volume subgroup and 70.1% versus 61.1% in the low-volume subgroup. Among the most common AEs, many were known toxicities related to docetaxel.
In patients with high-volume and high-risk/low-risk metastatic hormone-sensitive prostate cancer, treatment intensification with darolutamide, androgen-deprivation therapy, and docetaxel increased OS with a similar AE profile in the subgroups, consistent with the overall population.Media: see text.
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