Enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung ...cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy.
We conducted this double-blind, placebo-controlled, phase 3 trial to evaluate atezolizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat population.
A total of 201 patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval CI, 0.54 to 0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed.
The addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by F. Hoffmann-La Roche/Genentech; IMpower133 ClinicalTrials.gov number, NCT02763579 .).
To evaluate macular atrophy (MA) presence in the 24-month HARBOR study (NCT00891735) for neovascular age-related macular degeneration (AMD).
Post hoc analysis of a phase 3 multicenter, prospective, ...randomized, double-masked, active treatment–controlled clinical trial.
Evaluable subjects (N = 1095) with subfoveal choroidal neovascularization (CNV) secondary to neovascular AMD treated with ranibizumab 0.5 mg or 2.0 mg monthly or pro re nata (PRN).
Fluorescein angiograms (FAs) and color fundus photographs at baseline and months 3, 12, and 24 were retrospectively graded by masked graders for MA: well-defined areas of depigmentation with increased choroidal vessel visibility, diameter ≥250 μm, corresponding to flat areas of well-demarcated staining on FA, excluding atrophy associated with retinal pigment epithelium tears. Atrophy immediately within, adjacent, and nonadjacent to CNV lesions was included.
Macular atrophy incidence, best-corrected visual acuity (BCVA).
At baseline, MA was detected in 11.2% (123/1095) of study eyes. At month 24, 29.4% (229/778) of eyes without baseline atrophy had detectable MA. Eyes with and without baseline MA had significant mean BCVA gains from baseline at month 24 (letters 95% confidence interval: +6.7 4.1–9.3; +9.1 8.0–10.2, respectively). Among eyes with and without MA at month 24, mean month 24 BCVA was 62.0 60.3–63.7 and 64.7 63.2–66.3 letters, respectively. Baseline risk factors for month 24 MA presence included intraretinal cysts (hazard ratio HR, 2.45 1.76–3.42) and fellow eye atrophy (HR, 2.02 1.42–2.87); subretinal fluid was associated with a lower MA risk (HR, 0.50 0.33–0.74). Ranibizumab dose was not associated with MA development. Monthly versus PRN treatment trended toward an association with MA (HR, 1.29 0.99–1.68), but was not statistically significant.
New MA was detected in 29% of study eyes after 24 months of treatment. Clinically significant BCVA gains were achieved with MA present over 24 months. Baseline subretinal fluid absence, intraretinal cyst presence, and fellow eye atrophy presence were associated with month 24 MA presence. With existing data, the benefits of ranibizumab for neovascular AMD outweighed the risk of MA development over 24 months in HARBOR, although outcomes >2 years were not evaluated.
Background
IMbrave150 is a phase III trial that assessed atezolizumab + bevacizumab (ATEZO/BEV) versus sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (HCC) and demonstrated a ...significant improvement in clinical outcomes. Exploratory analyses characterized objective response rate (ORR), depth (DpR), and duration of response (DoR), and patients with a complete response (CR).
Methods
Patients were randomized 2:1 to intravenous ATEZO (1200 mg) + BEV (15 mg/kg) every 3 weeks or oral SOR (400 mg) twice daily. Tumors were evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and HCC‐modified RECIST (mRECIST). ORR by prior treatment and largest baseline liver lesion size, DoR, time to response (TTR), and complete response (TTCR) were analyzed.
Results
For both criteria, responses favored ATEZO/BEV versus SOR regardless of prior treatment and in patients with lesions ≥3 cm. Median TTR was 2.8 months per RECIST 1.1 (range: 1.2–12.3 months) and 2.8 months per mRECIST (range: 1.1–12.3 months) with ATEZO/BEV. Patients receiving ATEZO/BEV had a greater DpR, per both criteria, across baseline liver lesion sizes. Characteristics of complete responders were similar to those of the intent‐to‐treat population. In complete responders receiving ATEZO/BEV per mRECIST versus RECIST 1.1, respectively, median TTCR was shorter (5.5 vs. 7.0 months), mean baseline sum of lesion diameter was longer (5.0 SD, 5.1 vs. 2.6 SD, 1.4 cm), and mean largest liver lesion size was larger (4.8 SD, 4.2 vs. 2.3 SD, 1.0 cm).
Conclusions
These data highlight the improved ORR, DpR, and CR rates with ATEZO/BEV in unresectable HCC.
IMbrave150 is a randomized phase III trial that showed statistically significant and clinically meaningful improvements in overall survival and progression‐free survival with atezolizumab plus bevacizumab versus sorafenib. The post hoc analyses presented here further highlight the ability of ATEZO/BEV to improve overall response rates, depth of response, and complete response rates in unresectable hepatocellular carcinoma versus sorafenib.
Abstract Introduction Denosumab is a fully human monoclonal antibody that inhibits receptor activator of nuclear factor-kappa B ligand (RANKL), an essential mediator of osteoclast formation, ...function, and survival that has been shown to decrease bone turnover and increase bone mineral density (BMD) in treated patients. We assessed the long-term efficacy and safety of denosumab, and the effects of discontinuing and restarting denosumab treatment in postmenopausal women with low bone mass. Methods Postmenopausal women with a lumbar spine T -score of − 1.8 to − 4.0 or proximal femur T -score of − 1.8 to − 3.5 were randomized to denosumab every 3 months (Q3M; 6, 14, or 30 mg) or every 6 months (Q6M; 14, 60, 100, or 210 mg); placebo; or open-label oral alendronate weekly. After 24 months, patients receiving denosumab either continued treatment at 60 mg Q6M for an additional 24 months, discontinued therapy, or discontinued treatment for 12 months then re-initiated denosumab (60 mg Q6M) for 12 months. The placebo cohort was maintained. Alendronate-treated patients discontinued alendronate and were followed. Changes in BMD and bone turnover markers (BTM) as well as safety outcomes were evaluated. Results Overall, 262/412 (64%) patients completed 48 months of study. Continuous, long-term denosumab treatment increased BMD at the lumbar spine (9.4% to 11.8%) and total hip (4.0% to 6.1%). BTM were consistently suppressed over 48 months. Discontinuation of denosumab was associated with a BMD decrease of 6.6% at the lumbar spine and 5.3% at the total hip within the first 12 months of treatment discontinuation. Retreatment with denosumab increased lumbar spine BMD by 9.0% from original baseline values. Levels of BTM increased upon discontinuation and decreased with retreatment. Adverse event rates were similar among treatment groups. Conclusions In postmenopausal women with low BMD, long-term denosumab treatment led to gains in BMD and reduction of BTM throughout the course of the study. The effects on bone turnover were fully reversible with discontinuation and restored with subsequent retreatment.
To explore the visual acuity and anatomic outcomes over 24 months of patients with diabetic macular edema (DME) who showed a delayed anatomic response after 3 ranibizumab injections in the RIDE and ...RISE trials.
Analysis of data from RIDE and RISE, 2 phase III, parallel, randomized, multicenter, double-masked trials (ClinicalTrials.gov identifiers, NCT00473382 and NCT00473330).
Patients with DME (n = 681) who received monthly intravitreal ranibizumab 0.3-mg injections, ranibizumab 0.5-mg injections, or sham injections.
Patients were separated into 3 groups: delayed responders (ranibizumab-treated patients with ≤10% central foveal thickness CFT reduction after 3 injections), immediate responders (ranibizumab-treated patients with >10% CFT reduction after 3 injections), and sham recipients. Central foveal thickness was measured by time-domain optical coherence tomography, best-corrected visual acuity (BCVA) was measured by Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores, and diabetic retinopathy (DR) was measured by the standardized ETDRS severity scale (using fundus photographs).
Month-24 CFT, BCVA, and DR severity levels.
In RIDE and RISE, 9% to 10% of ranibizumab-treated eyes were delayed responders. At month 24, delayed responders had less CFT reduction (median, −102 μm) from baseline compared with immediate responders (median, −274 μm; P < 0.0001). Delayed responders gained a median of 10 letters at 24 months, similar to immediate responders (14 letters; P = 0.15). At month 24, DR improvement among the delayed responders (31% and 22% of patients with ≥2- or ≥3-step DR improvement, respectively) was comparable with that among immediate responders (42% and 17%, respectively; P = 0.21 and P = 0.48, respectively).
With continued treatment, at month 24, patients with DME with delayed anatomic response (≤10% CFT reduction) after 3 ranibizumab injections had visual acuity gains and DR improvement similar to those of patients with DME who had immediate anatomic response.
Denosumab was well tolerated and efficacious through 6 years of continuous treatment in postmenopausal women with low bone mass.
Context:
This is a study extension to evaluate the efficacy and safety ...of long-term treatment with denosumab in postmenopausal women with low bone mass.
Objective:
Our objective was to describe changes in bone mineral density (BMD) and bone turnover markers as well as safety with 6 yr of denosumab treatment.
Design:
We conducted an ongoing 4-yr, open-label, single-arm, extension study of a dose-ranging phase 2 trial. This paper reports a 2-yr interim analysis representing up to 6 yr of continuous denosumab treatment.
Setting:
This multicenter study was conducted at 23 U.S. centers.
Patients:
Of the 262 subjects who completed the parent study, 200 enrolled in the study extension and 178 (89%) completed the first 2 yr.
Intervention:
All subjects received denosumab 60 mg sc every 6 months.
Main Outcome Measures:
We evaluated BMD at the lumbar spine, total hip, femoral neck, and one third radius; biochemical markers of bone turnover; and safety, reported as adverse events.
Results:
Over a period of 6 yr, continuous treatment with denosumab resulted in progressive gains in BMD in postmenopausal women with low bone mass. Reduction in bone resorption was sustained over the course of continuous treatment. Independent of past treatment and discontinuation period, subjects demonstrated responsiveness to denosumab therapy as measured by BMD and bone turnover markers. The safety profile of denosumab did not change over time.
Conclusions:
In this study, denosumab was well tolerated and effective through 6 yr of continuous treatment in postmenopausal women with low bone mass.
BackgroundAtezolizumab is a treatment for locally advanced/metastatic urothelial carcinoma (mUC). However, its use in patients with renal insufficiency or UC with mixed variant histology (MVH) is not ...well characterized.ObjectiveTo report efficacy and safety of atezolizumab in these special subpopulations from an expanded access program (EAP).Design, setting, and participantsA total of 218 patients were enrolled at 36 US study sites (November 2015–August 2016), and the trial ended following the approval of atezolizumab by the US Food and Drug Administration. This post hoc analysis investigated outcomes in specific study subgroups.InterventionAtezolizumab 1200 mg was administered intravenously every 3 weeks until loss of clinical benefit, unacceptable toxicity, death, consent withdrawal, decision to discontinue, commercial availability, or study closure.Outcome measurements and statistical analysisResponse Evaluation Criteria in Solid Tumors V.1.1 responses and safety were evaluated by baseline renal function and histology.Results and limitationsObjective responses occurred in 0/6 (0%), 4/19 (21%), 1/27 (3.7%), and 12/62 (19%) of evaluable patients with creatinine clearance (CrCl) <30, 30–45, 45–60, and ≥60 mL/min, respectively, and stable disease was seen in three patients with CrCl <30 mL/min. Objective responses were seen in 13/102 patients (13%) with urothelial carcinoma (UC) histology only and in 4/12 patients (33%) with UC with MVH. Treatment-related adverse event frequencies ranged from 35% to 54% across the earlier indicated CrCl subgroups and they were also similar in patients with pure UC or UC with MVH (46%).ConclusionsIn this EAP mUC subgroup analysis, clinical benefit of atezolizumab occurred in patients with compromised renal function or MVH UC tumors. Safety was comparable across subgroups.Patient summaryWe examined the efficacy and safety of atezolizumab for UC in certain patients participating in an EAP. We found that responses to atezolizumab occurred, and safety was similar, in most patient subgroups with varying levels of kidney functioning or less common types of tumor tissue histology.
PDF
