Schizophrenia Tied to Increased Cardiovascular Disease Risk

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Schizophrenia is associated with a significantly higher risk of developing cardiovascular disease (CVD), with a more pronounced relationship in women, results of a new study suggested.

METHODOLOGY:

The observational study included 4,124,508 patients without a history of CVD, median age of 44 years, from a Japanese health claims database.
The primary outcome was a composite of myocardial infarction (MI), angina pectoris, stroke, heart failure, atrial fibrillation, and pulmonary embolism; secondary outcomes included these individual outcomes.
Researchers examined the association between schizophrenia and incident CVD in men and women and adjusted for age, body mass index, hypertension, diabetes, dyslipidemia, cigarette smoking, alcohol consumption, and physical inactivity in the final model.
They performed subgroup analyses by age (≥ 50 vs < 50 years), obesity, hypertension, diabetes, dyslipidemia, and smoking, as well as a series of sensitivity analyses to validate the primary results.

TAKEAWAY:

During a mean follow-up of 1288 days, 182,158 CVD diagnoses were recorded, with an incidence rate of 141.1 per 10,000 person-years in men and 112.0 per 10,000 person-years in women.
Compared with those without schizophrenia, CVD risk in those with the condition was higher among women than in men (hazard ratio [HR], 1.63 vs 1.42, respectively; P = .0049), which the authors write could be attributed to hormonal changes during pregnancy and menopause or different cardiovascular risk factors such as physical inactivity in women.
Among those with schizophrenia, HRs for individual outcomes with significant P values for men and women, respectively, included: 1.04 and 1.31 for MI; 1.33 and 1.53 for angina pectoris; 1.42 and 1.80 for heart failure; and 1.02 and 1.44 for atrial fibrillation.
Schizophrenia was linked to an increased risk for CVD in men and women in those under 50 and those 50 and older, and results were consistent across all other subgroups in sensitivity analyses.

IN PRACTICE:

Given the findings, “healthcare providers should incorporate routine screening and treatment of schizophrenia into standard clinical practice,” the investigators wrote. Psychiatrists and cardiologists should work together to prevent CVD, especially in women, they added.

SOURCE:

The study, led by Jin Komuro, MD, Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan, was published online on February 27, 2024, in the Journal of the American Heart Association.

LIMITATIONS:

This observational study demonstrates an association between schizophrenia and CVD, not causation. The accuracy of diagnoses in insurance claims databases is uncertain, and as the database used in this study mainly includes working-age patients, it’s unclear if the findings can be generalized. The study didn’t consider variables such as socioeconomic status that may affect the relationship between schizophrenia and CVD. Individuals with schizophrenia may have had poor adherence to treatment for conditions such as hypertension and diabetes, which could have influenced the results.

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial.

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IMPORTANCE: Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma.

OBJECTIVE: To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor.

DESIGN, SETTING, AND PARTICIPANTS: This was a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months’ follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023.

INTERVENTION: Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m2) or placebo. All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months.

MAIN OUTCOMES AND MEASURES: The primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only.

RESULTS: Among 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P = .02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo).

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favorable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology.

Small Molecule Activators of Mitochondrial Fusion Prevent Congenital Heart Defects Induced by Maternal Diabetes

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Highlights

•	Most CHD cases are attributed to nongenetic factors, whereas the mechanisms underlying nongenetic factor–induced CHDs are elusive. Maternal diabetes is one of the nongenetic factors inducing CHDs.
•	The study reveals an innovative epigenetic mechanism underlying maternal diabetes–induced CHDs.
•	Maternal diabetes-activated transcription factor FoxO3a increases miR-140 and miR-195, which in turn represses Mfn1 and Mfn2, leading to mitochondrial fusion defects and CHDs.
•	Two mitochondrial fusion activators, teriflunomide (an FDA-approved drug) and echinacoside (a naturally occurring compound), increase the expression level of Mfn1 and Mfn2, restore mitochondrial fusion, and prevent CHD formation. These 2 activators show potential value in preventing CHDs in diabetic pregnancy.

Summary

Most congenital heart defect (CHD) cases are attributed to nongenetic factors; however, the mechanisms underlying nongenetic factor–induced CHDs are elusive. Maternal diabetes is one of the nongenetic factors, and this study aimed to determine whether impaired mitochondrial fusion contributes to maternal diabetes–induced CHDs and if mitochondrial fusion activators, teriflunomide and echinacoside, could reduce CHD incidence in diabetic pregnancy. We demonstrated maternal diabetes-activated FoxO3a increases miR-140 and miR-195, which in turn represses Mfn1 and Mfn2, leading to mitochondrial fusion defects and CHDs. Two mitochondrial fusion activators are effective in preventing CHDs in diabetic pregnancy.

Introduction

The United States has the highest infant mortality rate, which is the basic measure of public health, among developed countries.¹ Congenital heart defects (CHDs) are the most common cause of infant death.² Furthermore, CHDs are the most prevalent birth defects, occurring in approximately 4 to 10 per 1,000 live births.² Epidemiological studies in CHD prevention suggest a controversial effect of maternal folic acid supplementation,³^,⁴ which is the only effective intervention to prevent neural tube defects, another type of potentially fatal birth defect. However, a mechanism-based means of preventing CHDs is still lacking.

Human epidemiological studies have demonstrated that the major contributing factors to the occurrence of CHDs are nongenetic factors.²^,⁵ Among all nongenetic factors that cause CHDs, maternal diabetes is the major factor.²^,⁶ The rate of CHDs in infants born to mothers with diabetes is approximately 4 to 6 times higher than mothers without diabetes.^6-8 More than 60 million women of reproductive age worldwide have diabetes, and this number will likely double by 2030 due to the current global epidemic of obesity.⁹ Even under the best clinical care, women with diabetes are still 3 to 4 times more likely to have a child with CHDs than women without diabetes.¹⁰ Thus, given these incidences and the lack of means to prevent CHDs, its occurrence is an unmet clinical need, and therefore uncovering the cellular and molecular events underlying its development will aid in the identification of effective preventions.

Here, using a maternal diabetes mouse model of CHDs, we show that this pathology occurs due to activation of the transcription factor FoxO3a, which stimulates expression of miR-140 and miR-195 that, in turn, represses mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2) expression, respectively. Treating this model with 2 activators of mitochondrial fusion, teriflunomide, a U.S. Food and Drug Administration (FDA)-approved drug, and echinacoside, a natural compound, we found prevention of CHDs. This amelioration correlated with re-expression of Mfn1 and Mfn2, improved mitochondrial dynamics and cell proliferation, and reduced apoptosis. Thus, pharmacological restoration of mitochondrial fusion may be an effective approach to reduce the risk of CHDs resulting from diabetic pregnancy.

Discussion

It is conventionally accepted that organ development is orchestrated from the cell nucleus and that the mitochondria simply follow along; however, a recent study demonstrated that mitochondria orchestrate developmental events of the mouse heart, and the disturbance of mitochondrial function contributes to CHD formation.¹⁶ Mitochondrial dynamics are governed by fusion and fission events essential for proper heart development.¹⁶ Mitochondria fuse via the function of Mfn1 and Mfn2. Deleting the Mfn1 and Mfn2 genes in early heart muscle cells results in severely underdeveloped hearts.¹⁶ Furthermore, mouse embryonic stem cells missing Mfn2 and Opa1 (optic atrophy protein 1), a mitochondrial fusion facilitator, do not develop into beating cardiomyocytes.¹⁶ Reduced mitochondrial fusion resulting from Mfn1 and Mfn2 deletion disrupts several signaling pathways implicated in CHDs.¹⁶ This evidence suggests that altered mitochondrial dynamics drive cardiac dysmorphogenesis.

Impaired mitochondrial fusion leads to mitochondrial dysfunction and subsequently alters cardiac morphogenesis. Mitochondrial dysfunction is an evident cellular defect in cardiomyocytes exposed to maternal diabetes.¹⁷^,²⁴ Intrinsic abnormalities are present in cardiomyocytes derived from inducible pluripotent stem cells of patients with CHDs that lack an underlying genetic cause,²⁵ suggesting that cell development is a key factor in cardiac morphogenesis. These cellular organelle defects continue to persist after the establishment of CHDs and may contribute to sustainable cardiomyocyte dysfunction in patients with CHD. The present study illustrates for the first time that maternal diabetes increases 2 key miRNAs that impair mitochondrial fusion and enhance mitochondrial fragmentation in mouse embryonic cardiomyocytes in vitro and in vivo.

miRNAs are critically involved in virtually all aspects of cardiac development and disease.²⁶ miR-1 overexpression disrupts mouse embryonic heart development,²⁷ and miR-133a overexpression in cardiomyocytes leads to decreased cell proliferation and the formation of cardiac septation defects.²⁸ The present study demonstrates that the upregulation of miR-140 and miR-195 mediates the teratogenicity of maternal diabetes leading to CHDs. During development, miR-140 is predominantly expressed in embryonic chondrocytes.²⁹ miR-140 induces cardiomyocyte apoptosis via the intrinsic mitochondrial pathway.¹⁴ In contrast to miR-140, miR-195 is expressed early in the developing human heart.³⁰ miR-195 inhibits cell proliferation and induces apoptosis by repressing multiple prosurvival proteins.³¹^,³² Multiple lines of evidence suggest that miR-140 and miR-195 always work together. They both trigger mitochondrial dysfunction,¹⁴^,³¹ participate in stem cell aging,³¹ and are elevated in adult heart diseases.³³ In agreement with the coherence between these 2 miRNAs, we found that deleting the mir140 gene or the mir195 gene significantly ameliorated maternal diabetes–induced CHDs, and that overexpressing these 2 miRNAs in the heart mimicked maternal diabetes in inducing CHDs.

The transcription factor FoxO3a is activated by maternal diabetes.²³ FoxO3a upregulates miRNAs in cancer cells.³⁴ In the present study, FoxO3a transcriptionally induced miR-140 and miR-195 expression and thus inhibited mitochondrial fusion in embryonic cardiomyocytes. FoxO3a reduces the size of cardiomyocytes in rats.³⁵ FoxO3a is a cell death trigger that acts through the mitochondrial apoptosis pathway in conditions of heart failure and hypertrophy.³⁶^,³⁷ Our previous study indicated that the deletion of FoxO3a could inhibit maternal diabetes–induced apoptosis in cardiac progenitor cells in vivo.³⁸ Here, we showed that Foxo3a gene deletion ameliorates maternal diabetes–induced CHDs by suppressing mitochondrial fragmentation and dysfunction. Thus, we reveal the downstream effectors of FoxO3a, miR-140 and miR-195, in defective heart development.

Mitochondrial fusion, a prosurvival event, maintains mitochondrial homeostasis by removing dysfunctional mitochondria.³⁹^,⁴⁰ Cells lacking both Mfn1 and Mfn2 have completely fragmented mitochondria with no detectable mitochondrial fusion.⁴⁰ Mitochondrial fusion is important for the maintenance of mitochondrial morphology, cell growth, membrane potential, and respiration.³⁹ Reduced fusion could be a key factor contributing to diabetes- or miRNA-induced mitochondrial dysfunction. Maternal diabetes induces cellular dysfunction in cells required for cardiac septation leading to CHDs.¹⁷^,²⁴ Enhanced mitochondrial fusion stimulates cell proliferation by promoting cell cycle progression.⁴¹ Cells with double knockout of Mfn1 and Mfn2 proliferate much slower than their corresponding wild-type counterparts.⁴² Here, we showed that reduced Mfn1 and Mfn2 expression cause cellular dysfunction and alterations in cardiac septation leading to CHDs under conditions of maternal diabetes exposure and miRNA overexpression.

Small molecule drugs are the pillars of traditional medicine. Teriflunomide, a small molecule compound, is approved by the FDA for use in the treatment of multiple sclerosis; however, studies also showed that teriflunomide could activate mitochondrial fusion. One study indicated that teriflunomide upregulates mitofusins and also induces mitochondrial elongation by depletion of the cellular pyrimidine pool secondary to the inhibition of dihydroorotate dehydrogenase.²⁰ Another study indicated that teriflunomide increases Mfn2 transcriptional activity and mitofusin mRNA levels in Hela cells.⁴³ Echinacoside, another small molecule compound, is currently being investigated for anti-apoptotic and neuroprotective effects.⁴⁴^,⁴⁵ Similarly, this compound also can function as a mitochondrial fusion activator. A study found that echinacoside selectively binds to the previously uncharacterized casein kinase 2 (CK2) α′ subunit (CK2α′) as a direct cellular target and allosterically regulates CK2α′ conformation to recruit basic transcription factor 3 (BTF3) to form a binary protein complex, and then the CK2α′/BTF3 complex facilitates β-catenin nuclear translocation to activate T-cell factor/lymphoid enhancer factor transcription factors and stimulates transcription of the mitochondrial fusion gene Mfn2.²¹ These findings are consistent with our current study. We demonstrated that teriflunomide and echinacoside, acting as mitochondrial fusion activators, increase the expression levels of Mfn1 and Mfn2 and improve mitochondrial fusion in cardiomyocytes under diabetic conditions, and in turn, prevent CHD formation in diabetic pregnancy. We did not observe any side effect of the 2 compounds in pregnant mice or embryos at the adopted dosage (15 mg/kg); however, we found teriflunomide often caused abortion at a higher dosage (30 mg/kg) in our preliminary study.

The STZ-induced type 1 diabetic embryopathy mouse model, which can mimic hyperglycemia in human maternal diabetes, is widely accepted in the field of maternal diabetes–induced birth defects.¹¹^,⁴⁶^,⁴⁷ STZ used to induce diabetes is not a complicating factor because STZ is cleared from the bloodstream rapidly (serum half-life is 5 minutes with no drug measurable by 2 hours),⁴⁸ and pregnancy is not established until 1 to 2 weeks after STZ injection.⁴⁹ Insulin treatment of STZ-induced diabetic embryopathy effectively reduces hyperglycemia and embryonic malformations,⁴⁹ indicating that hyperglycemia is the primary cause of teratogenicity and that pregestational STZ injections do not cause any toxicity to the developing embryo. In the current study, this mouse model produced 20% to 40% CHDs, including ventricular septum defect, persistent truncus arteriosus, transposition of the great arteries, and hypoplastic left heart syndrome, in embryos exposed to diabetes, whereas embryos from nondiabetic controls had zero CHDs. Among all the CHD cases, ventricular septum defect cases were the most common, which is almost identical to that in humans.⁶^,⁵⁰ In addition, we observed very few neural tube defect cases at E17.5 when embryos were harvested for CHD rate determination, as well as the infrequent cases of kidney defects and eye defects. We used 2 miRNA modified mouse models in this study, miR-140 global knockout and miR-195 conditional knockout mice, and did not observe any cardiac or noncardiac defects because of the deletion of each miRNA.

Unlike neural tube defects, which can be reduced by folate supplementation, prevention methods for CHDs are lacking. The present study reveals a mechanism-based method for the prevention of CHDs induced by nongenetic factors that are primarily causal factors in humans. Treatment of the diabetic pregnant dams with small molecule activators of mitochondrial fusion restored Mfn1 and Mfn2 expression at the transcriptional level and subsequently rescued mitochondrial fusion in cardiomyocytes. We also uncovered the molecular pathway that leads to the inhibition of mitochondrial fusion in the CHD models, thus providing new targets for the design of prevention approaches.

Conclusions

We conclude that reduced mitochondrial fusion is a key event in the formation of CHDs induced by either miR-195/miR-140 Tg expression or exposure to a maternal diabetic milieu. Maternal diabetes–activated FoxO3a increases miR-140 and miR-195, which in turn represses Mfn1 and Mfn2, leading to mitochondrial fusion defects and CHDs. Maternal treatment with either of teriflunomide and echinacoside restores Mfn1 and Mfn2 expression and mitochondrial fusion in cardiomyocytes of embryonic hearts exposed to diabetes, implicating that activating mitochondrial fusion could be a potent means to prevent CHDs induced by maternal nongenetic factors.

Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection

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Abstract

Background

Thrombolytic agents, including tenecteplase, are generally used within 4.5 hours after the onset of stroke symptoms. Information on whether tenecteplase confers benefit beyond 4.5 hours is limited.

Methods

We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving patients with ischemic stroke to compare tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) with placebo administered 4.5 to 24 hours after the time that the patient was last known to be well. Patients had to have evidence of occlusion of the middle cerebral artery or internal carotid artery and salvageable tissue as determined on perfusion imaging. The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death) at day 90. Safety outcomes included death and symptomatic intracranial hemorrhage.

Results

The trial enrolled 458 patients, 77.3% of whom subsequently underwent thrombectomy; 228 patients were assigned to receive tenecteplase, and 230 to receive placebo. The median time between the time the patient was last known to be well and randomization was approximately 12 hours in the tenecteplase group and approximately 13 hours in the placebo group. The median score on the modified Rankin scale at 90 days was 3 in each group. The adjusted common odds ratio for the distribution of scores on the modified Rankin scale at 90 days for tenecteplase as compared with placebo was 1.13 (95% confidence interval, 0.82 to 1.57; P=0.45). In the safety population, mortality at 90 days was 19.7% in the tenecteplase group and 18.2% in the placebo group, and the incidence of symptomatic intracranial hemorrhage was 3.2% and 2.3%, respectively.

Conclusions

Tenecteplase therapy that was initiated 4.5 to 24 hours after stroke onset in patients with occlusions of the middle cerebral artery or internal carotid artery, most of whom had undergone endovascular thrombectomy, did not result in better clinical outcomes than those with placebo. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups.

Intravenous thrombolytic therapy with alteplase has generally been the standard care for eligible patients within 4.5 hours after the onset of ischemic stroke.¹ One limitation for extending the time window for thrombolysis has been an increase in the incidence of intracranial hemorrhage. In a pooled analysis of nine randomized trials that selected patients with stroke on the basis of noncontrast computed tomography (CT) of the head and compared alteplase with placebo or open control (without a placebo group) administered no more than 6 hours after stroke onset, treatment with alteplase significantly increased the odds of symptomatic intracranial hemorrhage.² Although most previous trials of thrombolytic therapy have indicated that the benefit of treatment is dependent on the earliest possible time that reperfusion can be obtained,² a meta-analysis showed a benefit of alteplase administered during the 4.5-to-9-hour time window after stroke onset in selected patients who had evidence of viable tissue on CT perfusion imaging or perfusion–diffusion magnetic resonance imaging (MRI).³ This finding suggested that, in patients with favorable imaging profiles showing salvageable brain tissue, intravenous thrombolysis in an extended window may be safe and efficacious. However, the patients in these trials did not undergo endovascular thrombectomy, which has become the preferred treatment for patients with large-vessel occlusions and imaging evidence of salvageable tissue who can be treated within 24 hours after stroke onset.

Tenecteplase is a modified form of human tissue plasminogen activator that was approved in 2000 to reduce mortality among patients with acute myocardial infarction.⁴ Several trials have shown the noninferiority of tenecteplase to alteplase when treatment is begun within 4.5 hours after stroke onset,^5-8 and the most recent American Heart Association–American Stroke Association (AHA–ASA) guidelines for acute ischemic stroke indicate that tenecteplase is a reasonable alternative to alteplase in specific patient populations.¹

Data regarding the use of tenecteplase beyond 4.5 hours after symptom onset are limited. A trial of tenecteplase in patients who had stroke symptoms when they awoke, but who were not selected on the basis of CT perfusion imaging or perfusion–diffusion MRI, showed that tenecteplase therapy was not associated with better functional outcomes than placebo; however, safety results were similar to those of thrombolytic therapy given within 4.5 hours after onset.⁹ A proof-of-concept trial showed the feasibility of treatment with tenecteplase administered no more than 24 hours after stroke onset¹⁰ in patients with evidence of salvageable tissue on CT perfusion imaging.

The Thrombolysis in Imaging Eligible, Late Window Patients to Assess the Efficacy and Safety of Tenecteplase (TIMELESS) trial was designed to test the hypothesis that intravenous tenecteplase, initiated 4.5 to 24 hours after stroke onset, would provide a benefit in patients who had a large-vessel occlusion of the internal carotid artery or the first (M1) or second (M2) segments of the middle cerebral artery and had evidence of salvageable ischemic brain tissue identified on CT perfusion or MRI perfusion–diffusion studies. (The M1 segment is the main trunk, and the M2 segment the first-order branch of the main trunk.) In this trial, patients with occlusions of the internal carotid artery or the M1 segment were anticipated to receive standard-care endovascular thrombectomy in addition to tenecteplase or placebo, whereas the use of endovascular thrombectomy in patients with an occlusion of the M2 segment was at the discretion of the treating physician.

Discussion

The TIMELESS trial did not show a significant improvement in functional outcomes at 90 days in patients with stroke who had evidence of salvageable tissue on perfusion imaging and received tenecteplase 4.5 to 24 hours after the time they were last known to be well. Most patients also underwent endovascular thrombectomy (77.3%). The incidence of recanalization at 24 hours appeared to be higher with tenecteplase than with placebo, but the incidence of reperfusion was similar in the two groups at the end of the procedure.

Given the high proportion of patients who underwent endovascular thrombectomy and had a short interval between thrombolytic administration and arterial puncture, our trial resembles various trials that compared endovascular thrombectomy with or without preceding alteplase therapy^16-22 in a time window of up to 4.5 hours after onset. The time between the administration of the intravenous thrombolytic agent and arterial puncture in these trials was longer (median, 25 minutes; interquartile range, 15 to 39) than the time between the administration of tenecteplase and arterial puncture in the current trial (15 minutes; interquartile range, 3 to 25), but the incidence of recanalization before endovascular thrombectomy was similar. A meta-analysis with the use of individual patient data that included the addition of thrombolysis to thrombectomy did not show the noninferiority of direct endovascular thrombectomy to combined treatment with an intravenous thrombolytic agent and thrombectomy.²³

In the EXTEND-IA TNK trial,⁷ treatment with tenecteplase resulted in a higher incidence of reperfusion before thrombectomy and better functional outcome than alteplase therapy among patients with ischemic stroke treated within 4.5 hours after symptom onset and before endovascular thrombectomy. The median time from the initiation of intravenous thrombolysis with tenecteplase to arterial puncture was 42 minutes in the EXTEND-IA TNK trial, as compared with 15 minutes in our trial. One possible reason for the time difference was the larger proportion of patients in the EXTEND-IA TNK trial than in our trial who received tenecteplase at a center that was not capable of providing endovascular treatment before transfer. Our trial did not enroll enough patients at such centers to provide insights into the effect of tenecteplase in this patient population.

In this trial, we found no benefit in functional outcome with tenecteplase as compared with placebo administered 4.5 to 24 hours after symptom onset in patients with ischemic stroke who had been selected on the basis of a favorable perfusion-imaging profile, most of whom subsequently underwent endovascular therapy. The incidence of brain hemorrhage was similar in the two trial groups.

Source: NEJM

An Oral Interleukin-23–Receptor Antagonist Peptide for Plaque Psoriasis

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Abstract

Background

The use of monoclonal antibodies has changed the treatment of several immune-mediated inflammatory diseases, including psoriasis. However, these large proteins must be administered by injection. JNJ-77242113 is a novel, orally administered interleukin-23–receptor antagonist peptide that selectively blocks interleukin-23 signaling and downstream cytokine production.

Methods

In this phase 2 dose-finding trial, we randomly assigned patients with moderate-to-severe plaque psoriasis to receive JNJ-77242113 at a dose of 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily, or 100 mg twice daily or placebo for 16 weeks. The primary end point was a reduction from baseline of at least 75% in the Psoriasis Area and Severity Index (PASI) score (PASI 75 response; PASI scores range from 0 to 72, with higher scores indicating greater extent or severity of psoriasis) at week 16.

Results

A total of 255 patients underwent randomization. The mean PASI score at baseline was 19.1. The mean duration of psoriasis was 18.2 years, and 78% of the patients across all the trial groups had previously received systemic treatments. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 groups (37%, 51%, 58%, 65%, and 79% in the 25-mg once-daily, 25-mg twice-daily, 50-mg once-daily, 100-mg once-daily, and 100-mg twice-daily groups, respectively) than among those in the placebo group (9%), a finding that showed a significant dose–response relationship (P<0.001). The most common adverse events included coronavirus disease 2019 (in 12% of the patients in the placebo group and in 11% of those across the JNJ-77242113 dose groups) and nasopharyngitis (in 5% and 7%, respectively). The percentages of patients who had at least one adverse event were similar in the combined JNJ-77242113 dose group (52%) and the placebo group (51%). There was no evidence of a dose-related increase in adverse events across the JNJ-77242113 dose groups.

Conclusions

After 16 weeks of once- or twice-daily oral administration, treatment with the interleukin-23–receptor antagonist peptide JNJ-77242113 showed greater efficacy than placebo in patients with moderate-to-severe plaque psoriasis.

A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis

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Abstract

Background

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta–selective agonist in development for the treatment of NASH with liver fibrosis.

Methods

We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score.

Results

Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was −13.6% in the 80-mg resmetirom group and −16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group.

Conclusions

Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage.

Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer

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Abstract

BACKGROUND

The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib, in combination with fulvestrant therapy, prolongs progression-free survival among patients with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer. We report the results of a prespecified analysis of overall survival.

METHODS

We randomly assigned patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had progression or relapse during previous endocrine therapy to receive palbociclib plus fulvestrant or placebo plus fulvestrant. We analyzed overall survival; the effect of palbociclib according to the prespecified stratification factors of presence or absence of sensitivity to endocrine therapy, presence or absence of visceral metastatic disease, and menopausal status; the efficacy of subsequent therapies after disease progression; and safety.

RESULTS

Among 521 patients who underwent randomization, the median overall survival was 34.9 months (95% confidence interval [CI], 28.8 to 40.0) in the palbociclib–fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo–fulvestrant group (hazard ratio for death, 0.81; 95% CI, 0.64 to 1.03; P=0.09; absolute difference, 6.9 months). CDK4/6 inhibitor treatment after the completion of the trial regimen occurred in 16% of the patients in the placebo–fulvestrant group. Among 410 patients with sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib–fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo–fulvestrant group (hazard ratio, 0.72; 95% CI, 0.55 to 0.94; absolute difference, 10.0 months). The median duration of subsequent therapy was similar in the two groups, and the median time to the receipt of chemotherapy was 17.6 months in the palbociclib–fulvestrant group, as compared with 8.8 months in the placebo–fulvestrant group (hazard ratio, 0.58; 95% CI, 0.47 to 0.73; P<0.001). No new safety signals were observed with 44.8 months of follow-up.

CONCLUSIONS

Among patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had sensitivity to previous endocrine therapy, treatment with palbociclib–fulvestrant resulted in longer overall survival than treatment with placebo–fulvestrant. The differences in overall survival in the entire trial group were not significant.

In 2018, approximately 266,000 new cases of breast cancer are estimated to occur in women in the United States, with 41,000 deaths.¹ Of these, hormone-receptor–positive breast cancer is the most common disease subtype.² The cyclin-dependent kinases 4 and 6 (CDK4/6) are key promoters of tumor growth in hormone-receptor–positive breast cancer, cooperating with estrogen-receptor pathway activation.^3,4 Preclinical models of hormone-receptor–positive breast cancer were highly sensitive to the CDK4/6 inhibitor palbociclib (Ibrance, Pfizer),⁴ and in a subsequent phase 2 study (Palbociclib: Ongoing Trials in the Management of Breast Cancer [PALOMA]–1), palbociclib resulted in a progression-free survival benefit in patients with previously untreated, estrogen-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer.⁵ Subsequently, the randomized, phase 3 trial PALOMA-2 confirmed that palbociclib substantially prolonged progression-free survival, in combination with letrozole, as first-line therapy for estrogen-receptor–positive, HER2-negative advanced breast cancer (hazard ratio for disease progression or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72).⁶

In the phase 3 trial PALOMA-3, we assessed whether treatment with palbociclib, in combination with fulvestrant, prolonged progression-free survival among patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had disease progression after previous endocrine therapy. The primary aim of the trial was met, with the trial showing significantly longer progression-free survival with combination palbociclib–fulvestrant therapy than with placebo–fulvestrant (median, 11.2 months [95% CI, 9.5 to 12.9] vs. 4.6 months [95% CI, 3.5 to 5.6]; hazard ratio for disease progression or death, 0.50; 95% CI, 0.40 to 0.62; absolute difference, 6.6 months).^7-9

Palbociclib and other CDK4/6 inhibitors in combination with endocrine therapy have become a standard of care on the basis of prolonged progression-free survival.^5,10,11 However, long-term data regarding the effect of palbociclib on overall survival and the efficacy of subsequent therapy have been limited. Here, we report the results of a prespecified analysis of the PALOMA-3 trial in which we assessed the effect of palbociclib on overall survival and the efficacy of therapies administered after disease progression.

Methods

TRIAL DESIGN AND PATIENTS

We conducted this prospective, international, randomized, double-blind, placebo-controlled, phase 3 trial to compare treatment with palbociclib–fulvestrant with placebo–fulvestrant in women with hormone-receptor–positive, HER2-negative advanced breast cancer who had disease progression after previous endocrine therapy. Patients were randomly assigned, in a 2:1 ratio, to receive either palbociclib (at a dose of 125 mg, administered orally, once daily for 21 consecutive days, followed by 7 days off, to comprise a complete cycle of 28 days) plus fulvestrant (at a dose of 500 mg, administered as an intramuscular injection according to standard of care, every 14 days for the first three injections and then every 28 days) or placebo plus fulvestrant. Crossover between the two groups was not permitted.

Women were enrolled regardless of menopausal status; postmenopausal women were at least 60 years of age, had undergone bilateral oophorectomy, or were younger than 60 years of age and had had a cessation of regular menses for at least 12 consecutive months. Premenopausal or perimenopausal patients were required to receive concurrent goserelin for at least 4 weeks before the start of the trial intervention and to continue receiving it every 28 days for the duration of the trial intervention.

Randomization was stratified according to the presence or absence of documented sensitivity to previous endocrine therapy, the presence or absence of visceral metastatic disease, and menopausal status at trial entry. Sensitivity to previous endocrine therapy was defined as either a documented clinical benefit (complete response, partial response, or stable disease for ≥24 weeks) from at least one previous endocrine therapy regimen in the context of metastatic disease or the receipt of at least 24 months of adjuvant endocrine therapy before recurrence. Detailed methods of this trial have been reported previously.^7,8 The protocol, with the statistical analysis plan, is available with the full text of this article at NEJM.org.

END POINTS

The primary end point, investigator-assessed progression-free survival, was reported previously.^7,8 Overall survival, a prespecified key secondary end point, was defined as the time from randomization to death from any cause. Exploratory analyses included the investigator-assessed time receiving subsequent therapy (i.e., the time from randomization to the end of the immediate subsequent line of therapy after disease progression) and time from randomization to the receipt of chemotherapy. Safety data were updated with additional follow-up time.

OVERSIGHT

The trial was designed by an academic steering committee that included representatives of the sponsor (Pfizer). Data were gathered by representatives of the sponsor. All the authors confirm that the trial conformed to the protocol and attest to the accuracy and completeness of the data. All the authors and participating institutions have agreements with the sponsor regarding confidentiality of the data. The first author wrote the first draft of the manuscript. All the authors had full access to the data and were involved in interpreting the data, in writing and reviewing subsequent drafts of the manuscript, and in making the decision to submit the manuscript for publication. A professional medical writer provided editorial assistance and was paid by the sponsor. AstraZeneca provided fulvestrant and had no involvement with the data collection or analysis or with any aspect of the manuscript preparation.

The trial was approved by the institutional review board at each site, and all the patients provided written informed consent before enrollment. The trial was conducted according to the principles of Good Clinical Practice and the Declaration of Helsinki. The conduct of the trial was monitored by an academic steering committee.

STATISTICAL ANALYSIS

The median overall survival among women with advanced or metastatic breast cancer who are treated with fulvestrant monotherapy was assumed to be 24 months. The trial was powered for its primary end point, progression-free survival. The planned final analysis of overall survival was performed after approximately 60% data maturity (i.e., when death had occurred in 60% of the 521 patients who had undergone randomization), with one interim analysis of overall survival conducted at the time of the interim analysis of progression-free survival, when 28 deaths had occurred, and one interim analysis conducted when 112 deaths had occurred. The family-wise error rate was protected at the one-sided 0.025 level, with a hierarchical testing strategy between progression-free survival and overall survival.^12,13 The median overall survival was estimated with the use of the Kaplan–Meier method, and the significance was determined with the use of a one-sided log-rank test with stratification according to presence or absence of sensitivity to previous endocrine therapy and the presence or absence of visceral metastases at randomization in the intention-to-treat population. All the P values reported herein are two-sided. The prespecified significance threshold was a two-sided P value of 0.047, which was adjusted for the planned interim analyses. The rank-preserving structural-failure time method was used as a sensitivity analysis to evaluate the effect of crossover to receive a CDK4/6 inhibitor in the placebo–fulvestrant group after the completion of the trial intervention. The rank-preserving structural-failure time analysis is based on the intention-to-treat population and can provide a more accurate estimation of the treatment effect by correcting for crossover between groups.^14,15

Results

PATIENTS

A total of 521 patients were enrolled between October 7, 2013, and August 26, 2014 (Fig. S1 in the Supplementary Appendix, available at NEJM.org). A total of 347 patients were randomly assigned to the palbociclib–fulvestrant group and 174 to the placebo–fulvestrant group (intention-to-treat population). A total of 345 patients in the palbociclib–fulvestrant group and 172 in the placebo–fulvestrant group received at least one dose of the assigned intervention (safety population).

Double-blinding was maintained after both the primary analysis and the interim analysis. After a request from the investigator, unblinding occurred in 12 patients (3%) who received palbociclib and in 18 (10%) who received placebo. Most of these unblinding events (in 7 patients in the palbociclib–fulvestrant group and in 17 in the placebo–fulvestrant group) occurred after disease progression.

OVERALL SURVIVAL

Figure 1.Overall Survival in the Overall Population and According to Subgroup.

The data regarding overall survival were analyzed at a cutoff date of April 13, 2018, with a median follow-up of 44.8 months and 60% data maturity (310 deaths among 521 patients). A total of 201 deaths occurred in the palbociclib–fulvestrant group, and 109 deaths in the placebo–fulvestrant group. The median overall survival was 34.9 months (95% CI, 28.8 to 40.0) in the palbociclib–fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo–fulvestrant group. The stratified hazard ratio for death was 0.81 (95% CI, 0.64 to 1.03; P=0.09) (Figure 1A). The unstratified hazard ratio was 0.79 (95% CI, 0.63 to 1.00). The estimated rate of overall survival at 3 years in the Kaplan–Meier analysis was 50% (95% CI, 44 to 55) in the palbociclib–fulvestrant group and 41% (95% CI, 33 to 48) in the placebo–fulvestrant group.Figure 2.Overall Survival According to Patients’ Sensitivity to Previous Endocrine Therapy.

Subgroup analyses of overall survival were performed in prespecified subgroups (Figure 1B). The three prespecified stratification factors were the presence or absence of sensitivity to previous endocrine therapy, the presence or absence of visceral metastatic disease, and menopausal status. Among 410 patients with documented sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib–fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo–fulvestrant group (hazard ratio for death, 0.72; 95% CI, 0.55 to 0.94) (Figure 1B and Figure 2A). Among 111 patients without documented sensitivity to previous endocrine therapy (also referred to as intrinsic endocrine resistance), the median overall survival was 20.2 months (95% CI, 17.2 to 26.4) in the palbociclib–fulvestrant group and 26.2 months (95% CI, 17.5 to 31.8) in the placebo–fulvestrant group (hazard ratio, 1.14; 95% CI, 0.71 to 1.84; P=0.12 for interaction) (Figure 1B and Figure 2B). In the updated analysis of PALOMA-3, which was conducted at a data cutoff of October 23, 2015, patients with sensitivity to previous endocrine therapy had progression-free survival that was 7.8 months longer in the palbociclib–fulvestrant group than in the placebo–fulvestrant group (hazard ratio for disease progression or death, 0.46; 95% CI, 0.36 to 0.59), whereas patients with intrinsic endocrine resistance had progression-free survival that was 2.3 months longer (hazard ratio, 0.69; 95% CI, 0.43 to 1.09) (Fig. S2 in the Supplementary Appendix).

Among 311 patients with visceral metastatic disease, the median overall survival was 27.6 months (95% CI, 24.4 to 31.2) in the palbociclib–fulvestrant group and 24.7 months (95% CI, 20.8 to 31.8) in the placebo–fulvestrant group (hazard ratio for death, 0.85; 95% CI, 0.64 to 1.13) (Figure 1B). Among 210 patients without visceral metastatic disease, the median overall survival was 46.9 months (95% CI, 39.3 to could not be estimated) in the palbociclib–fulvestrant group and 35.4 months (95% CI, 24.6 to could not be estimated) in the placebo–fulvestrant group (hazard ratio, 0.69; 95% CI, 0.46 to 1.04; P=0.44 for interaction) (Figure 1B).

Among 413 postmenopausal patients, the median overall survival was 34.8 months (95% CI, 28.8 to 40.1) in the palbociclib–fulvestrant group and 27.1 months (95% CI, 22.8 to 32.1) in the placebo–fulvestrant group (hazard ratio for death, 0.73; 95% CI, 0.57 to 0.95) (Figure 1B, and Fig. S3A in the Supplementary Appendix). Among 108 premenopausal or perimenopausal patients, the median overall survival was 38.0 months (95% CI, 24.4 to could not be estimated) in the palbociclib–fulvestrant group and 38.0 months (95% CI, 22.2 to could not be estimated) in the placebo–fulvestrant group (hazard ratio, 1.07; 95% CI, 0.61 to 1.86; P=0.25 for interaction) (Figure 1B, and Fig. S3B in the Supplementary Appendix).

An exploratory subgroup analysis evaluated overall survival according to ESR1 and PIK3CA mutation status, as assessed in baseline circulating tumor DNA. The median overall survival was longer with palbociclib–fulvestrant than with placebo–fulvestrant among patients with baseline ESR1 mutations than among those without such mutations (absolute difference, 11.0 months among patients with ESR1 mutations and 4.7 months among those without such mutations; P=0.60 for interaction) (Figure 1B). The absolute between-group differences in overall survival were similar among patients with baseline PIK3CA mutations and those without such mutations (6.4 months and 5.8 months, respectively; P=0.64 for interaction) (Figure 1B).

EXPOSURE TO TRIAL INTERVENTION

Figure 3.Time from Randomization to the End of the Trial Intervention.

The median number of cycles of therapy received was 12 (interquartile range, 4 to 21) in the palbociclib–fulvestrant group and 5 (interquartile range, 2 to 12) in the placebo–fulvestrant group. The Kaplan–Meier estimate of the rate of patients continuing the trial intervention at 24 months was 23% (95% CI, 19 to 28) in the palbociclib–fulvestrant group and 10% (95% CI, 6 to 15) in the placebo–fulvestrant group, and the rate at 36 months was 14% (95% CI, 11 to 18) and 5% (95% CI, 3 to 9), respectively (Figure 3). At the time of the analysis, 35 patients (10%) were continuing to receive the trial intervention in the palbociclib–fulvestrant group (median duration, 45.4 months; range, 44.2 to 51.4), as compared with 6 patients (3%) in the placebo–fulvestrant group (median duration, 44.7 months; range, 44.2 to 45.6).

DISEASE PROGRESSION AFTER TRIAL INTERVENTION

Table 1.Systemic Anticancer Therapies Received as First, Second, and Third or Greater Lines of Subsequent Treatment by More Than 10% of the Patients in Either Trial Group Who Discontinued the Intervention.

In the intention-to-treat population, 389 patients (75%) received therapy after the end of trial intervention. The median number of lines of treatment received after disease progression was 2 (range, 1 to 10) in the palbociclib–fulvestrant group and 3 (range, 1 to 10) in the placebo–fulvestrant group. The type of subsequent treatment was similar in the two trial groups, except for subsequent CDK4/6 inhibitor treatment (Table 1). Approximately 40% of the patients in each group received endocrine-based therapy as the immediate subsequent line of treatment.

Although the protocol did not allow patients to cross over to receive palbociclib, treatment with a CDK4/6 inhibitor in the subsequent or following lines of treatment after the trial intervention occurred in 4% of patients in the palbociclib–fulvestrant group and 16% of those in the placebo–fulvestrant group (Table 1). We performed a sensitivity analysis to explore the effect of this crossover on overall survival. The rank-preserving structural-failure time analysis suggested a small decrease in overall survival in the placebo–fulvestrant group after correction for the crossover effect of 27 patients (median overall survival, 27.4 months [95% CI, 23.8 to 35.4]; stratified hazard ratio for death in the palbociclib–fulvestrant group vs. the crossover-corrected placebo–fulvestrant group, 0.78 [bootstrapped 95% CI, 0.61 to 1.04]; unstratified hazard ratio, 0.77 [bootstrapped 95% CI, 0.60 to 1.00]), as compared with a median overall survival of 28.0 months before adjustment.

TIME RECEIVING SUBSEQUENT LINE OF THERAPY

In exploratory analyses, we analyzed the time from randomization to the end of the immediate subsequent line of therapy after disease progression, which was 18.8 months (95% CI, 16.4 to 20.5) in the palbociclib–fulvestrant group and 14.1 months (95% CI, 12.0 to 16.7) in the placebo–fulvestrant group (hazard ratio, 0.68; 95% CI, 0.56 to 0.84; P<0.001). The time from randomization to the first use of chemotherapy after disease progression was 17.6 months (95% CI, 15.2 to 19.7) in the palbociclib–fulvestrant group, as compared with 8.8 months (95% CI, 7.3 to 12.7) in the placebo–fulvestrant group (hazard ratio, 0.58; 95% CI, 0.47 to 0.73; P<0.001). The duration of the immediate subsequent line of therapy, according to type of treatment, was similar in the palbociclib–fulvestrant group and the placebo–fulvestrant group. Details are provided in Figures S4 and S5 in the Supplementary Appendix.

ADVERSE EVENTS

The adverse-event profile of palbociclib–fulvestrant remained consistent with that in the primary analysis (Table S1 in the Supplementary Appendix).⁷ Neutropenia of grade 3 or 4 occurred in 70% of the patients receiving palbociclib–fulvestrant and in none of the patients receiving placebo–fulvestrant, anemia of grade 3 or 4 occurred in 4% and 2% of the patients, respectively, and thrombocytopenia of grade 3 or 4 occurred in 3% and none of the patients, respectively. Febrile neutropenia remained uncommon, occurring in 1% of the patients (3 of 345 patients) who received palbociclib–fulvestrant and in none of those who received placebo–fulvestrant. Nonhematologic adverse events of grade 3 or 4 were also uncommon. Events of grade 3 or 4 that occurred at a frequency of more than 2% of the patients in the palbociclib–fulvestrant group were infections (in 5% of the patients in the palbociclib–fulvestrant group and in 3% of those in the placebo–fulvestrant group), fatigue (in 3% and 1%, respectively), and elevation in the aspartate aminotransferase level (in 3% and 2%).

Discussion

Although the results of the analysis of overall survival did not meet the prespecified threshold for statistical significance, the addition of palbociclib to fulvestrant resulted in an absolute prolongation of overall survival of 6.9 months among patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had disease progression after previous endocrine therapy. This result is consistent with the significant prolongation in progression-free survival that was observed with the addition of palbociclib to fulvestrant (Fig. S6 in the Supplementary Appendix). Among patients with previous sensitivity to endocrine therapy, one of the largest subpopulations enrolled in the trial, overall survival was prolonged by 10.0 months.

Multiple studies have shown that the addition of CDK4/6 inhibitors to endocrine therapy results in substantially prolonged progression-free survival. Improvement has been observed in combination with aromatase inhibitors^6,16-18 and fulvestrant^7,19,20 for palbociclib, ribociclib, and abemaciclib therapy. A key issue has been the extent to which this benefit in progression-free survival translates to a prolongation of overall survival. In the PALOMA-3 trial, we found that the magnitude of improvement in progression-free survival (6.6 months longer with the addition of palbociclib to fulvestrant)⁹ translates directly to an improvement in overall survival of similar magnitude in the overall group of trial patients (6.9 months longer), but the difference did not reach statistical significance. This improvement was associated with a longer time from randomization to the end of the immediate subsequent line of therapy after disease progression and a longer time from randomization to the first use of chemotherapy after disease progression among patients treated with palbociclib–fulvestrant than among those who received placebo–fulvestrant. Furthermore, with this longer follow-up, a subgroup of patients who were treated with palbociclib–fulvestrant had a very long duration of disease control, with 14% of the patients continuing in the trial after 3 years of treatment with palbociclib–fulvestrant, as compared with 5% of those receiving placebo–fulvestrant.

Final data regarding overall survival from phase 3 trials of letrozole and CDK4/6 inhibitors are limited. These trials all have lower power for the statistical analysis of overall survival than for the statistical analysis of progression-free survival, and therefore the data presented in this article should be interpreted cautiously when deciding on the timing of CDK4/6 inhibitor therapy. Our data support the use of palbociclib–fulvestrant in patients with disease recurrence during endocrine therapy after at least 2 years of adjuvant therapy or in patients who received endocrine therapy alone for metastatic disease with clinical benefit. For patients for whom first-line aromatase inhibitor–based therapy is a standard of care or those who do not have a relapse while they are receiving an aromatase inhibitor, our findings do not inform the timing of palbociclib therapy.

The results regarding overall survival in the PALOMA-3 trial show the substantial challenges of finding a significant prolongation of overall survival in the context of a disease in which survival after disease progression is substantially longer than the time in the trial.²¹ To design a trial in this context that would detect a significant improvement in overall survival to result in a hazard ratio for death of 0.80 would have required a much larger trial. Accordingly, an 80% power calculation would involve more than 700 events, as compared with the approximate 46% power that results from the 310 deaths among the 521 patients who were enrolled in this trial. Future meta-analyses of CDK4/6 inhibitor studies may provide a more robust assessment of the effect of this class of drugs on overall survival, including in subgroups of patients. This trial also shows a further challenge of finding a significant benefit, because 16% of the patients in the placebo–fulvestrant group crossed over to receive a CDK4/6 inhibitor as subsequent therapy because of the commercial availability of this class of agents. Crossover to receive an investigational drug after disease progression may attenuate the observed advantage in overall survival²² and probably resulted in a modest prolongation of overall survival in the control group, thereby further reducing the power of the trial to show a significant benefit.

A planned subgroup analysis of overall survival regarding the three prespecified stratification factors identified the patients who derived the most benefit from palbociclib. In particular, patients with sensitivity to previous endocrine therapy had a substantial benefit, whereas those with intrinsic endocrine resistance had a limited benefit. This differential benefit in terms of overall survival closely mirrors the absolute prolongation of progression-free survival that was observed with palbociclib in these two populations. These data confirm that palbociclib was highly effective in augmenting responses in endocrine-sensitive cancers, but the effect may be more limited in tumors with intrinsic endocrine resistance. However, relatively few patients with intrinsic endocrine resistance were recruited in the trial, which limits the assessment of palbociclib in these patients.

Although palbociclib–fulvestrant resulted in a longer median overall survival than placebo–fulvestrant among postmenopausal patients but not among premenopausal or perimenopausal patients, this disparity can be attributed in part to the small size of the subgroup of premenopausal or perimenopausal patients and may also reflect variance in the proportion of patients with intrinsic endocrine resistance in the two subgroups. In the subgroup of premenopausal or perimenopausal patients, the percentage of patients with intrinsic endocrine resistance was higher than in the postmenopausal subgroup (30% vs. 19%).²³ Because patients with intrinsic endocrine resistance may have limited benefit from endocrine therapy in combination with palbociclib, the overall survival benefit is difficult to ascertain. Furthermore, an imbalance in certain prognostic factors between the palbociclib–fulvestrant group and the placebo–fulvestrant group in the subgroup of premenopausal or perimenopausal patients favored the control group. Premenopausal or perimenopausal patients who had been randomly assigned to the placebo–fulvestrant group had received fewer lines of previous therapy than those who had been randomly assigned to the palbociclib–fulvestrant group (lines of previous therapy, 0 or 1: 72% of the patients in the placebo–fulvestrant group vs. 58% of those in the palbociclib–fulvestrant group), and fewer patients were 40 years of age or younger (22% of patients in the placebo–fulvestrant group vs. 35% of those in the palbociclib–fulvestrant group).²³

The duration of the immediate subsequent line of therapy after disease progression after the completion of trial intervention was similar in the palbociclib–fulvestrant group and the placebo–fulvestrant group, which shows that standard treatments had similar efficacy after progression while patients were receiving palbociclib or placebo (Fig. S5 in the Supplementary Appendix). Research on the mechanisms of resistance to CDK4/6 inhibitors in the PALOMA-3 trial indicated that disease progression during palbociclib–fulvestrant treatment was due predominantly to endocrine resistance.^24,25 Analysis of circulating tumor DNA in plasma samples obtained at the end of the trial intervention revealed that the genetic profile at the end of the trial intervention was largely similar in patients treated with palbociclib and those who received placebo, with the exception of retinoblastoma (RB1) mutations that were selected in 5% of the patients who had progression during palbociclib treatment.²⁴ The data regarding overall survival in this trial suggest that the low rate of RB1 mutations selected by palbociclib has no overall detectable effect on either overall survival or sensitivity to subsequent therapies after progression during trial treatment.

Taken together, the data from the PALOMA-3 trial showed that palbociclib in combination with fulvestrant led to a 6.9-month prolongation of overall survival, although the finding did not reach significance in the intention-to-treat population. In the subgroup of patients with sensitivity to previous endocrine therapy, overall survival was 10 months longer with palbociclib–fulvestrant than with placebo–fulvestrant.

Nivolumab for Patients With High-Risk Oral Leukoplakia:A Nonrandomized Controlled Trial

Posted by zedie

Key Points

Question Can immune checkpoint therapy treat high-risk oral precancerous disease to prevent progression to oral squamous carcinoma?

Findings This phase 2 nonrandomized controlled trial treated 33 patients with high-risk oral proliferative verrucous leukoplakia with the programmed cell death 1 protein inhibitor nivolumab and demonstrated variable lesion regression by size and degree of dysplasia in response to therapy, while 27% of patients developed invasive oral cancer after nivolumab. All whole-exome sequenced patients who progressed to develop cancer had 9p21.3 chromosomal loss.

Meaning Nivolumab showed potential clinical activity in this immune checkpoint therapy trial for high-risk oral precancerous disease; future trials should prioritize cancer-free survival end points and biomarker stratification.

Abstract

Importance Proliferative verrucous leukoplakia (PVL) is an aggressive oral precancerous disease characterized by a high risk of transformation to invasive oral squamous cell carcinoma (OSCC), and no therapies have been shown to affect its natural history. A recent study of the PVL immune landscape revealed a cytotoxic T-cell–rich microenvironment, providing strong rationale to investigate immune checkpoint therapy.

Objective To determine the safety and clinical activity of anti–programmed cell death 1 protein (PD-1) therapy to treat high-risk PVL.

Design, Setting, and Participants This nonrandomized, open-label, phase 2 clinical trial was conducted from January 2019 to December 2021 at a single academic medical center; median (range) follow-up was 21.1 (5.4-43.6) months. Participants were a population-based sample of patients with PVL (multifocal, contiguous, or a single lesion ≥4 cm with any degree of dysplasia).

Intervention Patients underwent pretreatment biopsy (1-3 sites) and then received 4 doses of nivolumab (480 mg intravenously) every 28 days, followed by rebiopsy and intraoral photographs at each visit.

Main Outcomes and Measures The primary end point was the change in composite score (size and degree of dysplasia) from before to after treatment (major response [MR]: >80% decrease in score; partial response: 40%-80% decrease). Secondary analyses included immune-related adverse events, cancer-free survival (CFS), PD-1 ligand 1 (PD-L1) expression, 9p21.3 deletion, and other exploratory immunologic and genomic associations of response.

Results A total of 33 patients were enrolled (median [range] age, 63 [32-80] years; 18 [55%] were female), including 8 (24%) with previously resected early-stage OSCC. Twelve patients (36%) (95% CI, 20.4%-54.8%) had a response by composite score (3 MRs [9%]), 4 had progressive disease (>10% composite score increase, or cancer). Nine patients (27%) developed OSCC during the trial, with a 2-year CFS of 73% (95% CI, 53%-86%). Two patients (6%) discontinued because of toxic effects; 7 (21%) experienced grade 3 to 4 immune-related adverse events. PD-L1 combined positive scores were not associated with response or CFS. Of 20 whole-exome sequenced patients, all 6 patients who had progression to OSCC after nivolumab treatment exhibited 9p21.3 somatic copy-number loss on pretreatment biopsy, while only 4 of the 14 patients (29%) who did not develop OSCC had 9p21.3 loss.

Conclusions and Relevance This immune checkpoint therapy precancer nonrandomized clinical trial met its prespecified response end point, suggesting potential clinical activity for nivolumab in high-risk PVL. Findings identified immunogenomic associations to inform future trials in this precancerous disease with unmet medical need that has been difficult.

Introduction

Oral leukoplakia refers to a white plaque of variable cancer risk, having excluded other conditions, and affects up to 5% of the global population,¹ but only a small proportion of leukoplakia lesions will undergo malignant transformation.² Degree of epithelial dysplasia, lesion size, and tobacco history all influence the transformation rate.³ Proliferative verrucous leukoplakia (PVL) defines an aggressive subtype with a malignant transformation rate exceeding 10% per year, characterized by heterogeneous or verrucous lesions involving multiple oral subsites.⁴^–6 To date, no therapies have been shown to change the natural history of this severe oral precancerous disease,⁷^–9 reflecting a critical unmet medical need.

Studies of the immune landscape led to pivotal trials of anti–programmed cell death 1 protein (PD-1) therapy in recurrent/metastatic head and neck squamous cell carcinoma.¹⁰^–13 Our prior retrospective study revealed a cytotoxic T-cell–rich immune microenvironment in PVL.¹⁴ These findings together with immunosurveillance studies in the context of lung premalignancy and of various immune-oncology interventions in preclinical models¹⁵^–18 provided strong rationale for investigating PD-1/PD-1 ligand 1 (PD-L1) axis blockade in oral precancerous disease. Here we report the first (to our knowledge) trial to evaluate the safety and clinical activity of preventive anti–PD-1 therapy among patients with high-risk PVL.

Methods

Study Population

This was an open-label, single-group phase 2 trial conducted at the Dana-Farber Cancer Institute in Boston, Massachusetts (trial protocol in Supplement 1). Patients with high-risk oral leukoplakia defined by any of the following criteria were eligible: PVL with multifocal (≥2), contiguous 3 cm or greater, or a single lesion 4 cm or greater in largest diameter (2-3-4 rule) with epithelial dysplasia (any degree); PVL with 4-quadrant oral cavity involvement; at least 1 localized leukoplakia with moderate dysplasia, or erythroleukoplakia for which surgery was indicated but not feasible or the patient refused. Patients were 18 years or older and had an Eastern Cooperative Oncology Group performance status of 2 or lower. A history of surgically treated carcinoma in situ (CIS) or early-stage oral squamous cell carcinoma (OSCC) (American Joint Committee on Cancer Staging Manual, eighth edition, stages I or II) was permitted. Participants defined their race and ethnicity by self-identification. This was assessed given the potential for variation in interpreting the results of the study based on a majority of participants from 1 ethnic group and/or race given the epidemiology of the disease and the treatment center’s regional participant demographics. The trial was approved by the Dana-Farber/Harvard Cancer Center institutional review board (18-387), conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines, and registered nationally (NCT03692325). This study followed the Transparent Reporting of Evaluations With Nonrandomized Designs (TREND) reporting guideline.

Treatment

Following written informed consent, participants received nivolumab (480 mg intravenously) on day 1 of a 28-day cycle for 4 cycles. Immunosuppressive medications and doses of corticosteroids greater than 20-mg prednisone equivalent daily were prohibited unless used for immune-related toxicity management.

Assessments

Three weeks prior to the first dose of nivolumab and at monthly visits, patients underwent digital intraoral color photography to capture all leukoplakia lesions. Bidimensional measurements were obtained from up to 3 target lesions (per patient) as determined by 1 of 5 oral medicine investigators. Screening and posttreatment biopsies were performed by the same oral medicine investigator for consistency. Fresh tissue biopsies from all target lesions were mandatory at baseline and 30 days after the final dose of nivolumab. Pathologic specimens from each biopsy were examined by 2 experienced oral pathologists (V.Y.J. and K.S.W.) blinded to outcome data (or a third in cases of any scoring discrepancy). New or suspicious nontarget lesions or changes in target lesions could trigger rebiopsy at any point.

Response was assessed according to a modified composite scoring system (van der Waal classification)¹⁹ (eFigure 1 in Supplement 2). The sum of target lesion point scores (both clinical and pathologic) yielded a composite score. The percent change in composite score before and after treatment determined best overall response. Major response (MR) was a decrease of more than 80%, partial response (PR) a decrease of 40% to 80%, stable disease (SD) was neither an MR or PR, and progression of disease (PD) was defined as an increase of 10% or greater in the composite score or a CIS or OSCC diagnosis. Patients were followed up with clinical examinations every 3 to 4 months until study withdrawal or up to 5 years.

Safety

Safety evaluations included laboratory and adverse event (AE) assessments (National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0).²⁰ For patients who developed grade 3 or intolerable grade 2 immune-related AEs (irAEs), nivolumab treatment could be interrupted, delayed, or discontinued; certain grade 4 irAEs required discontinuation. AEs were captured up to 3 months after completion of nivolumab treatment.

Statistical Analysis

The primary end point was best overall response (MR + PR rate) as defined by the percent change in clinical-pathologic composite score. A 2-stage Simon optimal design was used. When more than 5 of 33 patients who were eligible and began protocol treatment had disease in response (assuming >1 patient with disease in response among the first 16 patients), there was 84.3% power to rule out a 10% and detect a 25% response rate (using a 1-sided exact binomial test, type I error rate of 10%). A response rate of 25% was targeted when considering the cumulative risk of serious irAEs.²¹

Secondary end points included safety and cancer-free survival (CFS), defined as the time from trial registration to OSCC or death due to any cause (participants alive without oral cancer were censored at last assessment). Based on studies of PD-L1 expression¹⁴^,22 and somatic 9p21 copy-number loss in advanced OSCC, lung, and other tumors,²³^,24 we conducted secondary analyses to evaluate the association of pretreatment dysplastic tissue PD-L1 expression and 9p21.3 deletion status with outcomes. Exploratory analyses included immunogenomic profiling using multiparametric flow cytometry and whole-exome sequencing (WES) detailed in the eMethods in Supplement 2.

The primary clinical activity population included all eligible patients who began protocol treatment. Response rate was summarized as a proportion with a corresponding 2-stage 95% CI. The distribution of CFS was estimated using the Kaplan-Meier method. Logistic regression and Cox proportional hazard models were used to estimate odds ratios (ORs) for best overall response and hazard ratios (HRs) for CFS, respectively. Fisher exact test was used to compare somatic copy-number alterations (SCNAs) and genomic subsets (2-sided). Wilcoxon signed rank test (paired data) and Wilcoxon rank-sum test (independent) were used to analyze both circulating and tissue-based immune profiling parameters (2-sided), using a Bonferroni-Dunn correction for tests of multiple comparisons. Data as of September 30, 2022, were analyzed. Data analysis used R, version 4.3.0 for Windows (R Foundation for Statistical Computing). A 2-sided P ≤ .05 indicates statistical significance.

Results

Between January 10, 2019, and December 13, 2021, the trial enrolled 33 patients. All began protocol treatment and were included in analyses (Figure 1A). Median (range) age was 63 (32-80) years, with a slight majority of female individuals (18 [55%]), and many were smokers (16 [48%]) (Table 1). Eight (24%) had a history of surgically treated early-stage OSCC. Median (range) disease-free interval for those with a head and neck cancer prior to trial entry was 10.5 (0.3-195.0) months. A median of 4 cycles of therapy were received (12% of patients received fewer than all 4 doses).

Twelve patients (36%) (95% CI, 20.4%-54.8%) demonstrated a best overall response of MR or PR, with 3 (9%) demonstrating a greater than 80% reduction in composite score (Table 2). Among individual patients, 2 (6%) had complete resolution of at least 1 target lesion. Sixteen (48%) had SD, and 4 patients (12%) had a best response of PD (Figure 1B and D). Three of the patients with a best response of PD developed OSCC in a target lesion identified on their end-of-treatment biopsy, and the other experienced an increase in the severity of dysplasia in a buccal gingiva target lesion resulting in greater than 20% composite score increase. No patient developed CIS. Six additional patients with a best response other than PD later developed OSCC (eTable 1 in Supplement 2); of note, 6 of the 9 who developed OSCC had a history of early-stage OSCC, and 3 of 12 responders (25%) later developed OSCC. Among the 9 patients with an OSCC event, median (range) time from trial registration to a first OSCC event was 6.6 (1.3-24.3) months, and median time from the last dose of nivolumab to the development of OSCC was 3.7 months. Eight of 9 events were in target lesions.

At a median (range) follow-up of 21.1 (5.4-43.6) months, median CFS had not been reached (NR) (95% CI, 24.3 months to NR) with a 2-year CFS of 72.8% (95% CI, 52.6%-85.5%) (Figure 2). There were 9 CFS events (27.3%) and no deaths (all OSCC events). No clinical or pathologic features appeared to be associated with CFS except a history of early-stage OSCC (HR, 13.53; 95% CI, 3.3-55.5) (eTable 2 in Supplement 2). The median CFS for patients with a prior oral cavity cancer diagnosis was 1.3 months (95% CI, 6.2-12.1), and for patients without a history of OSCC, the median was not reached.

Fatigue was the most common AE (18 [55%]), followed by oral pain (11 [33%]) and diarrhea (9 [27%]) (eTable 3 in Supplement 2). Seven patients (21%) developed grade 3 to 4 AEs, which later resolved. One patient without a cardiac history had atypical chest pain after a half-marathon after cycle 1 and had an elevated troponin T level; cardiologic evaluation clarified a low suspicion for immune-related myocarditis, and the patient resumed treatment. Two patients developed immune-related hepatitis. One patient developed immune-related colitis 5 months after completion of therapy.

All pretreatment dysplastic specimens were evaluable for PD-L1 combined positive score (CPS) testing. Scores ranged from 0 to 80 (eFigure 2A and B in Supplement 2), with 22 (67%) demonstrating a CPS of 1 or greater. No significant difference was observed in PD-L1 CPS scores among responders vs nonresponders (12.5 vs 5, P = .21), and patients with CPS 20 or greater vs less than 20 were not significantly more likely to respond (OR, 4.29; 95% CI, 0.83-25.94) (eTable 4 in Supplement 2).

Multiparametric flow on paired dysplastic tissue before and after treatment revealed that CD8⁺ T cells showed greater activation (CD69) and immune checkpoint LAG3 coexpression after treatment, with increased LAG3 expression among patients with pretreatment 9p21.3 loss of heterozygosity profiles. Among paired peripheral blood samples, PD-1 expression on both circulating CD4⁺ and CD8⁺ T cells decreased significantly (both adjusted P < .001), while CD38 increased on CD8⁺ T cells (adjusted P < .001) (supporting data in eFigure 2C in Supplement 2).

A subset of 23 patients (70%) had adequate tissue for WES. Twenty pairs of paired peripheral blood and oral dysplastic tissue passed quality controls. Pretreatment median (range) tumor mutational burden was 3.4 (1.4-8.0) mutations per megabase and was similar regardless of response (3.6 vs 2.8, P = .63) and among patients who developed cancer vs not (3.9 vs 2.9, P = .51) (Figure 3A). Genomic driver alterations were similar in patients who developed OSCC vs not. Missense mutations in PIK3CA were common. SCNAs revealed a range of complex allelic-imbalance profiles, primarily focal deletions, most frequently observed at 1q44 (Figure 3B). Only 9p21.3 deletion yielded statistically significant differences between patients who developed OSCC and those who did not. Of 10 patients whose pretreatment tissue sequencing showed 9p21.3 copy-number loss, 6 (60%) later developed OSCC, whereas none of the 10 patients without 9p21.3 loss developed OSCC (P = .01).

Discussion

We present the first (to our knowledge) trial demonstrating the potential efficacy of PD-1 immune checkpoint blockade among patients with high-risk oral precancerous disease. Our data suggest that PD-1 inhibition may yield clinical-pathologic regression in some patients. While some chemoprevention trials have yielded short-term responses to reverse or mute oral carcinogenesis, no therapeutic agents have demonstrated an improvement in CFS, and rates of progression to cancer range from 10% to 30%.⁷^–9,25^–28

PVL is an uncommon variant of leukoplakia, occurring in less than 1% of adults, which is aggressive and challenging to treat²⁹^,30 largely due to nonhomogeneous, multifocal lesions, and with the histologic hallmarks being corrugated hyperkeratosis and verrucous hyperplasia with variable dysplasia.⁵^,31^,32 Some degree of dysplasia was required in our trial with the aim of selecting the highest-risk lesions. Our previous retrospective cohort of patients with PVL suggested a 2-year CFS of 82%.¹⁴ In the present trial, we observed a 2-year CFS of 73%; however, we designed the trial with stringent entry criteria, requiring biopsy-proven dysplasia and permitting a history of OSCC. Notably, CFS was a secondary end point in our trial, and the sample size and median follow-up time were limited. It is plausible that our preliminary CFS rate would have been similar without immunotherapy exposure, supporting the need for randomized data. Three patients who had a response during the trial later developed OSCC, suggesting that our scoring system and response definitions may not adequately predict CFS. The prognostic impact of tumor size may not be readily generalizable to precancerous lesions, and a 1-tier change in histopathology (degree of dysplasia) may not be an optimal outcome measurement. As compared to prior chemoprevention trials, our rate of progression to cancer (27%) was comparable,⁷^–9,25^–28 while response was defined in prior studies primarily based on lesion size and not histologic change.

Of 9 OSCC events, 6 (67%) were among patients with prior early-stage OSCC with a short median time to failure (<4 months). Including patients with prior cancer events added some heterogeneity to the trial population, but we thought it was important to include them given their recurrence risk.³³ Exclusion of patients with prior oral cancer has been implemented in some chemoprevention studies,²⁷^,28,34^,35 but in the Erlotinib Prevention of Oral Cancer (EPOC) trial,⁷ 60% of patients had prior OSCC. That study followed a prevention-adjuvant therapy convergent design³⁶ under the assumption that high-risk patients with oral premalignant lesions and resected cancers share molecular alterations for prevention and could be studied in similar settings.²³^,37^,38 The cancer events among the patients in the current trial were most often pT1 lesions, but structured follow-up may have identified cancers earlier with a bias toward earlier biopsy. Longer follow-up in a larger randomized trial design will be needed to identify a time-to-event or survival benefit. It is unclear whether immunotherapy favorably affects the pathologic severity of future oral cancer events.

We acknowledge that novel pathologic criteria were required to evaluate clinical activity in this first oral precancer immune checkpoint therapy (ICT) prevention trial, as more traditional response criteria would not apply. We chose a modified composite scoring method to quantify response as a function of lesion size and dysplasia across multiple sites, recognizing that analyzing percent changes in composite score can be limited by small sample size and variability in scores. To limit interobserver variability, we required digital intraoral photography with bidimensional measurements and structured pathologic examination among 2 to 3 oral pathologists. We recognize that distinguishing mild dysplasia from hyperkeratosis can be subject to interpretation, and most of the cohort (73%) had mild dysplasia at baseline. Further, we observed a mix of lesion size and/or histologic changes in response to therapy among individual patients. We appreciate that multifocal lesions may have affected response assessments, but we would not expect spontaneous clinical regression in PVL in the absence of an effective therapy. A time-to-event CFS end point may be more generalizable and have broader clinical applicability. It is also worth noting that the trial population had limited racial and ethnic diversity, and many patients traveled to our center for treatment, which introduced some component of socioeconomic bias. This not only has potential treatment outcome implications, but also may influence tolerance and affordability.

A major concern for this ICT trial was safety, as we treated patients who did not have documented oral cancer. Frequently reported AEs were in line with prior head and neck cancer study populations more broadly.¹⁰^–13 We observed some increase in grade 3 to 4 AEs (21.2%), although we permitted a history of autoimmune disease, and all higher-grade irAEs resolved in time with no deaths. These findings need to be weighed carefully against the potential for clinical activity, given concern for a narrow therapeutic risk-benefit ratio.

Patients with PD-L1 CPS scores of 20 or greater in PVL were not more likely to respond (as has been observed in advanced OSCC¹¹), but this could be due to sample size limitations and/or scoring criteria (CPS is validated on invasive cancers); future studies will need to explore this further. Circulating CD4⁺/CD8⁺ T cells displayed significantly increased CD38 and reduced PD-1 expression following treatment, confirming on-target blockade of PD-1 and T-cell activation. An immune phenotype indicative of activation and/or reinvigoration was also observed on CD8⁺ T cells in oral dysplastic lesions, where surface expression of CD69 and LAG-3 were elevated in posttreatment samples.

Genomic studies of precancers have been limited by adequate tissue availability from small biopsies. Therefore, prior studies generally assessed single genes and/or allelic-imbalance using microsatellite markers, detecting 9p21.3 loss of heterozygosity in approximately 45% of patients with PVL, depending on the number of markers used.³⁹ To our knowledge, this is the first study using WES in PVL, which revealed a range of complex SCNA and allelic-imbalance profiles. Recent data from several groups have found that 9p deletions encompassing 9p21 are significant and selective predictors of ICT resistance in advanced OSCC and lung cancer.²³^,24,40^,41 This may be due to deletions encompassing the type I interferon gene cluster,⁴² which is often co-deleted with the tumor suppressor CDKN2A, highlighting a key mechanism of immune evasion.⁴³ In our immunogenomic studies, only pretreatment 9p21.3 deletion yielded statistically significant differences: 6 of 10 patients with 9p21.3 deletion in baseline biopsies later developed cancer. We have previously shown that 9p21.3 copy-number loss is generally a focal event in oral precancer⁴⁴ and associated with an immune-cold signal in OSCC²³ that is enhanced by larger deletions extending to the telomeric band at 9p24.1.⁴⁰ We speculate that resistance to the PD-1 inhibitor in this aggressive oral precancerous disease trial may have arisen during ICT resulting from increasing 9p deletion size to encompass 9p24.1, leading to low expression of the therapeutic target (PD-L1) and other immune gene depletion.²³^,40^,45 PD-L1 is encoded by the CD274 gene, which is located on 9p24.1, close to 9p21, and is often co-deleted in advanced human papillomavirus–negative head and neck squamous cell carcinoma and lung cancers.⁴²^,44

Limitations

This study has limitations. We thought it was important to include patients with prior cancer events given their risk but recognize that this added some heterogeneity to the study population. This trial was single group and single center, using a novel clinical and pathologic scoring system to assess immunotherapy response in a hard-to-study oral precancer population. A lack of randomization or use of a time-to-event end point is another limiting factor to acknowledge.

Conclusions

We report the first (to our knowledge) nonrandomized clinical trial of ICT in patients with precancerous disease, specifically patients with high-risk oral precancer, to mitigate progression to OSCC. This trial met its primary response end point, but few patients had complete lesion regression. Other studies using immunotherapy to treat patients with high-risk oral premalignant lesions are ongoing.⁴⁶^,47 Recognizing the limitations and complexity of measuring treatment outcomes in precancer trials, for the first time, we demonstrate potential clinical activity and acceptable safety with the use of ICT in a population with high-risk precancer. A next step would be to consider a larger, precision immunotherapy randomized clinical trial favoring CFS as a primary outcome and stratified by prior history of early-stage treated OSCC and 9p21.3 loss.

Source: JCO

Nine-Week Versus One-Year Trastuzumab for Early Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: 10-Year Update of the ShortHER Phase III Randomized Trial

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Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

We present the final analysis of the phase III noninferiority, randomized ShortHER trial comparing 9 weeks versus 1 year of adjuvant trastuzumab with chemotherapy in patients with human epidermal growth factor receptor 2–positive (HER2+) early breast cancer (BC). Women with HER2+ BC were randomly assigned to anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or 9-week trastuzumab (arm B, short). Here, we report the second coprimary end point overall survival (OS), updated disease-free survival (DFS), and outcomes according to hormone receptor status, age, and nodal status. At a median follow-up of 9 years, 10-year DFS is 77% versus 78% in the long versus short arm, respectively. Ten-year OS is 89% versus 88% in the long versus short arm, respectively. 10-year DFS rates in the long versus short arm according to nodal status are N0 81% versus 85%; N1-3 77% versus 79%; and N4+ 63% versus 53%. Ten-year OS rates in long versus short arm according to nodal status are N0 89% versus 95%%; N1-3 92% versus 89%; and N4+ 84% versus 64%. The updated analysis of the ShortHER trial shows that 1-year trastuzumab is the standard treatment for patients with HER2+ early BC as noninferiority cannot be claimed. However, numerically, the differences for the patients at low or intermediate risk (N0/N1-3) is negligible, while patients with N4+ have a clear benefit with 1-year trastuzumab.

Introduction

The multicenter, investigator-driven, phase III randomized noninferiority ShortHER study compared 9 weeks (short arm) versus 1 year (long arm) of adjuvant trastuzumab combined with chemotherapy in patients with human epidermal growth factor receptor 2–positive (HER2+) early breast cancer (BC). The first primary end point was the event-driven analysis of disease-free survival (DFS). The HR was 1.13 (90% CI, 0.89 to 1.42) and the noninferiority could not be claimed as the upper border of CI crossed the upper limit of 1.29 chosen as the noninferiority margin.¹

In the present paper, we report the final analysis, including the coprimary end point of overall survival (OS), of the ShortHER trial. The planned event-driven analysis for DFS of this study has been previously published.¹

Methods

Study Design

The ShortHER trial was a multicenter, investigator-driven, phase III randomized noninferiority study conducted in Italy within the frame of a clinical research program launched by AIFA (Agenzia Italiana del Farmaco [Italian Medicines Agency]) to improve the efficiency of the National Health System. The trial was approved by local ethical committees, and conducted in compliance with the principles of Good Clinical Practice and the Declaration of Helsinki. An independent data monitoring committee monitored the study. Patients provided written informed consent before enrollment.

Participants

Women age 18-75 years with surgically resected, HER2-positive BC were eligible. Women had to have node positivity, or in case of node negativity, at least one additional risk factor: pT size >2 cm, grade 3, lymphovascular invasion, Ki-67 >20%, age younger than 35 years, or hormone receptor–negative (estrogen receptor and progesterone receptor <10%).

Procedures

Eligible patients were stratified according to nodal status and hormone receptor status, and randomly assigned through a web-based system. Chemotherapy in arm A (long) consisted of AC (doxorubicin 60 mg/sqm + cyclophosphamide 600 mg/sqm) or EC (epidoxorubicin 90 mg/sqm + cyclophosphamide 600 mg/sqm) administered once every 3 weeks for four courses followed by paclitaxel 175 mg/sqm or docetaxel 100 mg/sqm once every 3 weeks for four courses. Trastuzumab was administered once every 3 weeks for 18 doses, starting with the first taxane dose (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter). Chemotherapy in arm B (short) consisted of docetaxel 100 mg/sqm once every 3 weeks for three courses followed by FEC (fluorouracil 600 mg/sqm, epidoxorubicin 60 mg/sqm, and cyclophosphamide 600 mg/sqm) administered once every 3 weeks for three courses. Trastuzumab was administered once per week for 9 weeks, starting concomitantly with docetaxel (4 mg/kg loading dose at first week, and 2 mg/kg thereafter). When indicated, radiation therapy and hormonal therapy according to local standard were carried out at the end of chemotherapy.

The primary end point was DFS with OS as a coprimary end point.

Statistical Analyses

This study is designed to assess whether a shorter trastuzumab administration is noninferior to the long one in respect with DFS. An HR <1.29 was set as a noninferiority margin. After amendment because of low recruitment, the sample size was reduced to 1,252 patients with 198 events with a power of 0.56. The Bayesian analysis was planned at the beginning of the study.

Top Studies in Neurology From 2023

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New Drugs in Alzheimer’s and ALS

Number one: monoclonal antibodies against beta amyloid for the treatment of early Alzheimer’s disease. For two monoclonal antibodies, lecanemab and donanemab, there was efficacy in slowing the disease progression. In practical terms, these two treatments pose significant problems. First, for diagnosis, you need PET-CT. The therapy has to be done via IV regularly, every 2 weeks or every 4 weeks. There are a number of side effects, which need MRI control, and the treatment is very expensive. We have, at present, no infrastructure for treating these patients. We also have a number of monoclonal antibodies that were not effective.

Number two: amyotrophic lateral sclerosis. There is a small subgroup, 1%-2% of patients, who have mutations in the SOD1 gene. There is now a new antisense oligonucleotide called tofersen, which reduces the concentration of SOD1 [protein] in the cerebrospinal fluid. There is a clinical phase 2 trial ongoing for efficacy.

Epilepsy, MS, and Gliomas

Number three: modern antiepileptic drugs taken during pregnancy in females with epilepsy. There is a study that showed that modern antiepileptic drugs like lamotrigine and levetiracetam have no effect on cognitive function in children aged 3 years. Remember, valproic acid and topiramate are clearly contraindicated in females with epilepsy during pregnancy.

Number four: There is an interesting disease called radiologically isolated syndrome. These are patients who get an MRI for whatever reason and they have signs of multiple sclerosis. We have two placebo-controlled studies for dimethyl fumarate and teriflunomide showing that you can delay the onset of the first episode of the disease compared with placebo.

The fifth study is a study in low-grade gliomas. There is a dual inhibitor of the mutated enzymes, IDH1 and IDH2, and this is called vorasidenib. This drug clearly improves the prognosis of patients with low-grade gliomas, and this is the first time that there is an effective treatment.

Migraine, Back Pain, and Stroke Treatments

Number six is the issue of triptan nonresponders in acute migraine attacks. The companies that produce the gepants and lasmiditan claim that up to 30% or 40% of patients are nonresponders to triptans. A study from the German Migraine Registry showed that triptan nonresponders do not exist if patients are given the opportunity to try three different triptans.

Number seven: We have very effective monoclonal antibodies against CGRP for the prevention of migraine, but 30% of patients will not respond. There is hope because there is another molecule involved in migraine, which is called PACAP. At the International Headache Congress, there was a placebo-controlled study that showed that a monoclonal antibody against PACAP is superior to placebo. We hope that this might be effective in people who do not respond to monoclonal antibodies against CGRP.

Number eight: acute back and neck pain. A large study from Australia clearly showed that opioids are not superior to placebo, and they should not be used also to avoid addiction.

Number nine: thrombectomy for large ischemic strokes. We were afraid to treat these patients out of fear of an increased risk for intracerebral hemorrhage, but this is not the case. There is a tension study with 253 patients that clearly shows that thrombectomy is superior to standard of care. We now have three studies showing that thrombectomy is also effective for large ischemic strokes, with only a small increase in intracerebral hemorrhage.

Remote Ischemic Conditioning

Finally, in 2022, there was a large study from China showing that remote ischemic conditioning in acute stroke might be effective. This is done by intermittent ischemia in the upper extremities. Now there is a new study in Europe with 1500 patients, which showed no benefit of remote ischemic conditioning, even if the treatment was started on the way to the hospital.

Dear colleagues, I’ve discussed 10 important publications and studies from 2023 which have impact for the treatment of our patients in neurology. I’m Christoph Diener from the medical faculty of University Duisburg-Essen.

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Schizophrenia is associated with a significantly higher risk of developing cardiovascular disease (CVD), with a more pronounced relationship in women, results of a new study suggested.

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BACKGROUND

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New Drugs in Alzheimer’s and ALS

Epilepsy, MS, and Gliomas

Migraine, Back Pain, and Stroke Treatments

Remote Ischemic Conditioning

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