Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy.

Cancer immunotherapy can induce long lasting responses in patients with metastatic cancers of a wide range of histologies. Broadening the clinical applicability of these treatments requires an improved understanding of the mechanisms limiting cancer immunotherapy. The interactions between the immune system and cancer cells are continuous, dynamic, and evolving from the initial establishment of a cancer cell to the development of metastatic disease, which is dependent on immune evasion. As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.

Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer.

Combining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/ß-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction. This is accompanied by suppression of MYC signaling and an increase in the T cell chemoattractant CCL5. Use of this combination treatment schema in mouse models of NSCLC reverses tumor immune evasion and modulates T cell exhaustion state towards memory and effector T cell phenotypes. Key correlative science metrics emerge for an upcoming clinical trial, testing enhancement of immune checkpoint therapy for NSCLC.

Inhibitory receptors and ligands beyond PD-1, PD-L1 and CTLA-4: breakthroughs or backups.

Although immunotherapeutics targeting the inhibitory receptors (IRs) CTLA-4, PD-1 or PD-L1 have made substantial clinical progress in cancer, a considerable proportion of patients remain unresponsive to treatment. Targeting novel IR-ligand pathways in combination with current immunotherapies may improve clinical outcomes. New clinical immunotherapeutics target T cell-expressed IRs (LAG-3, TIM-3 and TIGIT) as well as inhibitory ligands in the B7 family (B7-H3, B7-H4 and B7-H5), although many of these targets have complex biologies and unclear mechanisms of action. With only modest clinical success in targeting these IRs, current immunotherapeutic design may not be optimal. This Review covers the biology of targeting novel IR-ligand pathways and the current clinical status of their immunotherapeutics, either as monotherapy or in combination with antibody to PD-1 or to its ligand PD-L1. Further understanding of the basic biology of these targets is imperative to the development of effective cancer immunotherapies.

Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells.

Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.

De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors.

The tumor microenvironment confers profound resistance to anti-cancer immunotherapy. By targeting LIGHT, a member of the TNF superfamily of cytokines, to tumor vessels via a vascular targeting peptide (VTP), we developed a reagent with the dual ability to modulate the angiogenic vasculature and to induce tertiary lymphoid structures (TLSs). LIGHT-VTP triggered the influx of endogenous T cells into autochthonous or syngeneic tumors, which are resistant to immunotherapy. LIGHT-VTP in combination with checkpoint inhibition generated a large number of intratumoral effector and memory T cells with ensuing survival benefits, while the addition of anti-tumor vaccination achieved maximal therapeutic efficacy. Thus, the combination treatments stimulated the trafficking of pre-existing endogenous effector T cells as well as their intratumoral activation and were more successful than current immunotherapies, which fail due to tumor-intrinsic resistance mechanisms.

Analysis of a Therapeutic Antibody Cocktail Reveals Determinants for Cooperative and Broad Ebolavirus Neutralization.

Structural principles underlying the composition of protective antiviral monoclonal antibody (mAb) cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic mAb cocktail against Ebola virus. We systematically analyzed the antibody repertoire in human survivors and identified a pair of potently neutralizing mAbs that cooperatively bound to the ebolavirus glycoprotein (GP). High-resolution structures revealed that in a two-antibody cocktail, molecular mimicry was a major feature of mAb-GP interactions. Broadly neutralizing mAb rEBOV-520 targeted a conserved epitope on the GP base region. mAb rEBOV-548 bound to a glycan cap epitope, possessed neutralizing and Fc-mediated effector function activities, and potentiated neutralization by rEBOV-520. Remodeling of the glycan cap structures by the cocktail enabled enhanced GP binding and virus neutralization. The cocktail demonstrated resistance to virus escape and protected non-human primates (NHPs) against Ebola virus disease. These data illuminate structural principles of antibody cooperativity with implications for development of antiviral immunotherapeutics.

Brain-restricted mTOR inhibition with binary pharmacology.

On-target-off-tissue drug engagement is an important source of adverse effects that constrains the therapeutic window of drug candidates1,2. In diseases of the central nervous system, drugs with brain-restricted pharmacology are highly desirable. Here we report a strategy to achieve inhibition of mammalian target of rapamycin (mTOR) while sparing mTOR activity elsewhere through the use of the brain-permeable mTOR inhibitor RapaLink-1 and the brain-impermeable FKBP12 ligand RapaBlock. We show that this drug combination mitigates the systemic effects of mTOR inhibitors but retains the efficacy of RapaLink-1 in glioblastoma xenografts. We further present a general method to design cell-permeable, FKBP12-dependent kinase inhibitors from known drug scaffolds. These inhibitors are sensitive to deactivation by RapaBlock, enabling the brain-restricted inhibition of their respective kinase targets.

PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program.

Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection1. Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1+TCF1+ stem-like CD8+ T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+ T cells that resemble highly functional effector CD8+ T cells seen after an acute viral infection. The generation of these qualitatively superior CD8+ T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1+TCF1+ stem-like CD8+ T cells, also referred to as precursors of exhausted CD8+ T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8+ T cells emerging from the stem-like CD8+ T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25-CD122-CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer2,3, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.

Neoadjuvant relatlimab and nivolumab in resectable melanoma.

Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma1. We investigated this regimen in patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate2. The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57%. No grade 3-4 immune-related adverse events were observed in the neoadjuvant setting. The 1- and 2-year recurrence-free survival rate was 100% and 92% for patients with any pathologic response, compared to 88% and 55% for patients who did not have a pathologic response (P = 0.005). Increased immune cell infiltration at baseline, and decrease in M2 macrophages during treatment, were associated with pathologic response. Our results indicate that neoadjuvant relatlimab and nivolumab induces a high pCR rate. Safety during neoadjuvant therapy is favourable compared to other combination immunotherapy regimens. These data, in combination with the results of the RELATIVITY-047 trial1, provide further confirmation of the efficacy and safety of this new immunotherapy regimen.

Rational Cancer Treatment Combinations: An Urgent Clinical Need.

We are witnessing several revolutionary technological advances in cancer. These innovations have not only contributed to a growing understanding of the tumor and its microenvironment but also uncovered an increasing array of new therapeutic targets. For most advanced cancers, therapy resistance limits the benefit of single-agent therapies. Therefore, some 5,000 clinical trials are ongoing globally to probe the clinical benefit of new combination treatments. However, the possibilities to combine individual treatments dramatically outnumber the patients available to enroll in clinical trials. This comes at a potential cost of missed opportunities, clinical failure, avoidable toxicity, insufficient patient accrual, and financial loss. A solution may be to design combination therapies more rationally, which are informed by fundamental biological and mechanistic insight. We will discuss some successes and failures of current treatment combinations, as well as interesting emerging preclinical concepts that warrant clinical exploration.

Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.

BACKGROUND: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear. METHODS: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with higher scores reflecting better outcomes), was assessed by means of centralized adjudication. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after randomization. RESULTS: A total of 514 patients were assigned to receive argatroban (59 patients), eptifibatide (227 patients), or placebo (228 patients). All the patients received intravenous thrombolysis (70% received alteplase, and 30% received tenecteplase), and 225 patients (44%) underwent endovascular thrombectomy. At 90 days, the mean (±SD) utility-weighted modified Rankin scale scores were 5.2±3.7 with argatroban, 6.3±3.2 with eptifibatide, and 6.8±3.0 with placebo. The posterior probability that argatroban was better than placebo was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, -1.51±0.51) and that eptifibatide was better than placebo was 0.041 (posterior mean difference, -0.50±0.29). The incidence of symptomatic intracranial hemorrhage was similar in the three groups (4% with argatroban, 3% with eptifibatide, and 2% with placebo). Mortality at 90 days was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8%). CONCLUSIONS: In patients with acute ischemic stroke treated with intravenous thrombolysis within 3 hours after symptom onset, adjunctive treatment with intravenous argatroban or eptifibatide did not reduce poststroke disability and was associated with increased mortality. (Funded by the National Institute of Neurological Disorders and Stroke; MOST ClinicalTrials.gov number, NCT03735979.).

Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D.

BACKGROUND: In a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear. METHODS: In this phase 2b, open-label trial, we randomly assigned patients to receive peginterferon alfa-2a alone (180 µg per week) for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 µg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. All the patients were followed for 48 weeks after the end of treatment. The primary end point was an undetectable level of hepatitis D virus (HDV) RNA at 24 weeks after the end of treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group. RESULTS: A total of 24 patients received peginterferon alfa-2a alone, 50 received 2 mg and 50 received 10 mg of bulevirtide plus peginterferon alfa-2a, and 50 received 10 mg of bulevirtide monotherapy. At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15 to 50; P<0.001). At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group, in 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia. The majority of adverse events were of grade 1 or 2 in severity. CONCLUSIONS: The combination of 10-mg bulevirtide plus peginterferon alfa-2a was superior to bulevirtide monotherapy with regard to an undetectable HDV RNA level at 24 weeks after the end of treatment. (Funded by Gilead Sciences; MYR 204 ClinicalTrials.gov number, NCT03852433.).

Oral Nirmatrelvir-Ritonavir as Postexposure Prophylaxis for Covid-19.

BACKGROUND: Clinical trials of treatments for coronavirus disease 2019 (Covid-19) have not shown a significant benefit of postexposure prophylaxis. METHODS: We conducted a phase 2-3 double-blind trial to assess the efficacy and safety of nirmatrelvir-ritonavir in asymptomatic, rapid antigen test-negative adults who had been exposed to a household contact with Covid-19 within 96 hours before randomization. The participants were randomly assigned in a 1:1:1 ratio to receive nirmatrelvir-ritonavir (300 mg of nirmatrelvir and 100 mg of ritonavir) every 12 hours for 5 days or for 10 days or matching placebo for 5 or 10 days. The primary end point was the development of symptomatic SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, confirmed on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) or rapid antigen testing, through 14 days in participants who had a negative RT-PCR test at baseline. RESULTS: A total of 2736 participants were randomly assigned to a trial group - 921 to the 5-day nirmatrelvir-ritonavir group, 917 to the 10-day nirmatrelvir-ritonavir group, and 898 to the placebo group. Symptomatic, confirmed SARS-CoV-2 infection developed by day 14 in 2.6% of the participants in the 5-day nirmatrelvir-ritonavir group, 2.4% of those in the 10-day nirmatrelvir-ritonavir group, and 3.9% of those in the placebo group. In each nirmatrelvir-ritonavir group, the percentage of participants in whom symptomatic, confirmed SARS-CoV-2 infection developed did not differ significantly from that in the placebo group, with risk reductions relative to placebo of 29.8% (95% confidence interval [CI], -16.7 to 57.8; P = 0.17) in the 5-day nirmatrelvir-ritonavir group and 35.5% (95% CI, -11.5 to 62.7; P = 0.12) in the 10-day nirmatrelvir-ritonavir group. The incidence of adverse events was similar across the trial groups, with dysgeusia being the most frequently reported adverse event (in 5.9% and 6.8% of the participants in the 5-day and 10-day nirmatrelvir-ritonavir groups, respectively, and in 0.7% of those in the placebo group). CONCLUSIONS: In this placebo-controlled trial, postexposure prophylaxis with nirmatrelvir-ritonavir for 5 or 10 days did not significantly reduce the risk of symptomatic SARS-CoV-2 infection. (Funded by Pfizer; ClinicalTrials.gov number, NCT05047601.).

Cefepime-Taniborbactam in Complicated Urinary Tract Infection.

BACKGROUND: Carbapenem-resistant Enterobacterales species and multidrug-resistant Pseudomonas aeruginosa are global health threats. Cefepime-taniborbactam is an investigational ß-lactam and ß-lactamase inhibitor combination with activity against Enterobacterales species and P. aeruginosa expressing serine and metallo-ß-lactamases. METHODS: In this phase 3, double-blind, randomized trial, we assigned hospitalized adults with complicated urinary tract infection (UTI), including acute pyelonephritis, in a 2:1 ratio to receive intravenous cefepime-taniborbactam (2.5 g) or meropenem (1 g) every 8 hours for 7 days; this duration could be extended up to 14 days in case of bacteremia. The primary outcome was both microbiologic and clinical success (composite success) on trial days 19 to 23 in the microbiologic intention-to-treat (microITT) population (patients who had a qualifying gram-negative pathogen against which both study drugs were active). A prespecified superiority analysis of the primary outcome was performed after confirmation of noninferiority. RESULTS: Of the 661 patients who underwent randomization, 436 (66.0%) were included in the microITT population. The mean age of the patients was 56.2 years, and 38.1% were 65 years of age or older. In the microITT population, 57.8% of the patients had complicated UTI, 42.2% had acute pyelonephritis, and 13.1% had bacteremia. Composite success occurred in 207 of 293 patients (70.6%) in the cefepime-taniborbactam group and in 83 of 143 patients (58.0%) in the meropenem group. Cefepime-taniborbactam was superior to meropenem regarding the primary outcome (treatment difference, 12.6 percentage points; 95% confidence interval, 3.1 to 22.2; P = 0.009). Differences in treatment response were sustained at late follow-up (trial days 28 to 35), when cefepime-taniborbactam had higher composite success and clinical success. Adverse events occurred in 35.5% and 29.0% of patients in the cefepime-taniborbactam group and the meropenem group, respectively, with headache, diarrhea, constipation, hypertension, and nausea the most frequently reported; the frequency of serious adverse events was similar in the two groups. CONCLUSIONS: Cefepime-taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem. (Funded by Venatorx Pharmaceuticals and others; CERTAIN-1 ClinicalTrials.gov number, NCT03840148.).

Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks.

Crosstalk and complexity within signaling pathways and their perturbation by oncogenes limit component-by-component approaches to understanding human disease. Network analysis of how normal and oncogenic signaling can be rewired by drugs may provide opportunities to target tumors with high specificity and efficacy. Using targeted inhibition of oncogenic signaling pathways, combined with DNA-damaging chemotherapy, we report that time-staggered EGFR inhibition, but not simultaneous coadministration, dramatically sensitizes a subset of triple-negative breast cancer cells to genotoxic drugs. Systems-level analysis-using high-density time-dependent measurements of signaling networks, gene expression profiles, and cell phenotypic responses in combination with mathematical modeling-revealed an approach for altering the intrinsic state of the cell through dynamic rewiring of oncogenic signaling pathways. This process converts these cells to a less tumorigenic state that is more susceptible to DNA damage-induced cell death by reactivation of an extrinsic apoptotic pathway whose function is suppressed in the oncogene-addicted state.

Development of an aptamer capable of multidrug resistance reversal for tumor combination chemotherapy.

Multidrug resistance (MDR) is a major factor in the failure of many forms of tumor chemotherapy. Development of a specific ligand for MDR-reversal would enhance the intracellular accumulation of therapeutic agents and effectively improve the tumor treatments. Here, an aptamer was screened against a doxorubicin (DOX)-resistant human hepatocellular carcinoma cell line (HepG2/DOX) via cell-based systematic evolution of ligands by exponential enrichment. A 50 nt truncated sequence termed d3 was obtained with high affinity and specificity for HepG2/DOX cells. Multidrug resistance protein 1 (MDR1) is determined to be a possible recognition target of the selected aptamer. Aptamer d3 binding was revealed to block the MDR of the tumor cells and increase the accumulation of intracellular anticancer drugs, including DOX, vincristine, and paclitaxel, which led to a boost to the cell killing of the anticancer drugs and lowering their survival of the tumor cells. The aptamer d3-mediated MDR-reversal for effective chemotherapy was further verified in an in vivo animal model, and combination of aptamer d3 with DOX significantly improved the suppression of tumor growth by treating a xenograft HepG2/DOX tumor in vivo. This work demonstrates the feasibility of a therapeutic DNA aptamer as a tumor MDR-reversal agent, and combination of the selected aptamer with chemotherapeutic drugs shows great potential for liver cancer treatments.

Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression.

BACKGROUND: The benefits and risks of augmenting or switching antidepressants in older adults with treatment-resistant depression have not been extensively studied. METHODS: We conducted a two-step, open-label trial involving adults 60 years of age or older with treatment-resistant depression. In step 1, patients were randomly assigned in a 1:1:1 ratio to augmentation of existing antidepressant medication with aripiprazole, augmentation with bupropion, or a switch from existing antidepressant medication to bupropion. Patients who did not benefit from or were ineligible for step 1 were randomly assigned in step 2 in a 1:1 ratio to augmentation with lithium or a switch to nortriptyline. Each step lasted approximately 10 weeks. The primary outcome was the change from baseline in psychological well-being, assessed with the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales (population mean, 50; higher scores indicate greater well-being). A secondary outcome was remission of depression. RESULTS: In step 1, a total of 619 patients were enrolled; 211 were assigned to aripiprazole augmentation, 206 to bupropion augmentation, and 202 to a switch to bupropion. Well-being scores improved by 4.83 points, 4.33 points, and 2.04 points, respectively. The difference between the aripiprazole-augmentation group and the switch-to-bupropion group was 2.79 points (95% CI, 0.56 to 5.02; P = 0.014, with a prespecified threshold P value of 0.017); the between-group differences were not significant for aripiprazole augmentation versus bupropion augmentation or for bupropion augmentation versus a switch to bupropion. Remission occurred in 28.9% of patients in the aripiprazole-augmentation group, 28.2% in the bupropion-augmentation group, and 19.3% in the switch-to-bupropion group. The rate of falls was highest with bupropion augmentation. In step 2, a total of 248 patients were enrolled; 127 were assigned to lithium augmentation and 121 to a switch to nortriptyline. Well-being scores improved by 3.17 points and 2.18 points, respectively (difference, 0.99; 95% CI, -1.92 to 3.91). Remission occurred in 18.9% of patients in the lithium-augmentation group and 21.5% in the switch-to-nortriptyline group; rates of falling were similar in the two groups. CONCLUSIONS: In older adults with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole improved well-being significantly more over 10 weeks than a switch to bupropion and was associated with a numerically higher incidence of remission. Among patients in whom augmentation or a switch to bupropion failed, changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were similar. (Funded by the Patient-Centered Outcomes Research Institute; OPTIMUM ClinicalTrials.gov number, NCT02960763.).

Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer.

BACKGROUND: Patients with prostate cancer who have high-risk biochemical recurrence have an increased risk of progression. The efficacy and safety of enzalutamide plus androgen-deprivation therapy and enzalutamide monotherapy, as compared with androgen-deprivation therapy alone, are unknown. METHODS: In this phase 3 trial, we enrolled patients with prostate cancer who had high-risk biochemical recurrence with a prostate-specific antigen doubling time of 9 months or less. Patients were randomly assigned, in a 1:1:1 ratio, to receive enzalutamide (160 mg) daily plus leuprolide every 12 weeks (combination group), placebo plus leuprolide (leuprolide-alone group), or enzalutamide monotherapy (monotherapy group). The primary end point was metastasis-free survival, as assessed by blinded independent central review, in the combination group as compared with the leuprolide-alone group. A key secondary end point was metastasis-free survival in the monotherapy group as compared with the leuprolide-alone group. Other secondary end points were patient-reported outcomes and safety. RESULTS: A total of 1068 patients underwent randomization: 355 were assigned to the combination group, 358 to the leuprolide-alone group, and 355 to the monotherapy group. The patients were followed for a median of 60.7 months. At 5 years, metastasis-free survival was 87.3% (95% confidence interval [CI], 83.0 to 90.6) in the combination group, 71.4% (95% CI, 65.7 to 76.3) in the leuprolide-alone group, and 80.0% (95% CI, 75.0 to 84.1) in the monotherapy group. With respect to metastasis-free survival, enzalutamide plus leuprolide was superior to leuprolide alone (hazard ratio for metastasis or death, 0.42; 95% CI, 0.30 to 0.61; P<0.001); enzalutamide monotherapy was also superior to leuprolide alone (hazard ratio for metastasis or death, 0.63; 95% CI, 0.46 to 0.87; P = 0.005). No new safety signals were observed, with no substantial between-group differences in quality-of-life measures. CONCLUSIONS: In patients with prostate cancer with high-risk biochemical recurrence, enzalutamide plus leuprolide was superior to leuprolide alone with respect to metastasis-free survival; enzalutamide monotherapy was also superior to leuprolide alone. The safety profile of enzalutamide was consistent with that shown in previous clinical studies, with no apparent detrimental effect on quality of life. (Funded by Pfizer and Astellas Pharma; EMBARK ClinicalTrials.gov number, NCT02319837.).

A Phase 2 Trial of Peresolimab for Adults with Rheumatoid Arthritis.

BACKGROUND: Peresolimab is a humanized IgG1 monoclonal antibody designed to stimulate the endogenous programmed cell death protein 1 (PD-1) inhibitory pathway. Stimulation of this pathway would be a novel approach to the treatment of patients with autoimmune or autoinflammatory diseases. METHODS: In this phase 2a, double-blind, randomized, placebo-controlled trial, we assigned, in a 2:1:1 ratio, adult patients with moderate-to-severe rheumatoid arthritis who had had an inadequate response to, a loss of response to, or unacceptable side effects with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) or to biologic or targeted synthetic DMARDs to receive 700 mg of peresolimab, 300 mg of peresolimab, or placebo intravenously once every 4 weeks. The primary outcome was the change from baseline to week 12 in the Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP). The DAS28-CRP ranges from 0 to 9.4, with higher scores indicating more severe disease. The primary comparison was between the 700-mg group and the placebo group. Secondary outcomes included the percentages of patients with American College of Rheumatology 20 (ACR20), ACR50, and ACR70 responses - defined as improvements from baseline of 20%, 50%, and 70% or more, respectively, in the numbers of tender and swollen joints and in at least three of five important domains - at week 12. RESULTS: At week 12, the change from baseline in the DAS28-CRP was significantly greater in the 700-mg peresolimab group than in the placebo group (least-squares mean change [±SE], -2.09±0.18 vs. -0.99±0.26; difference in change, -1.09 [95% confidence interval, -1.73 to -0.46]; P<0.001). The results of the analyses of secondary outcomes favored the 700-mg dose over placebo with respect to the ACR20 response but not with respect to the ACR50 and ACR70 responses. Adverse events were similar in the peresolimab and placebo groups. CONCLUSIONS: Peresolimab showed efficacy in a phase 2a trial in patients with rheumatoid arthritis. These results provide evidence that stimulation of the PD-1 receptor has potential efficacy in the treatment of rheumatoid arthritis. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04634253.).

Second-Line Switch to Dolutegravir for Treatment of HIV Infection.

BACKGROUND: Data to inform the switch from a ritonavir-boosted protease inhibitor (PI) to dolutegravir in patients living with human immunodeficiency virus (HIV) infection who do not have genotype information and who have viral suppression with second-line therapy containing a ritonavir-boosted PI have been limited. METHODS: In a prospective, multicenter, open-label trial conducted at four sites in Kenya, we randomly assigned, in a 1:1 ratio, previously treated patients without genotype information who had viral suppression while receiving treatment containing a ritonavir-boosted PI to either switch to dolutegravir or continue the current regimen. The primary end point was a plasma HIV type 1 RNA level of at least 50 copies per milliliter at week 48, assessed on the basis of the Food and Drug Administration snapshot algorithm. The noninferiority margin for the between-group difference in the percentage of participants who met the primary end point was 4 percentage points. Safety up to week 48 was assessed. RESULTS: A total of 795 participants were enrolled, with 398 assigned to switch to dolutegravir and 397 assigned to continue taking their ritonavir-boosted PI; 791 participants (397 in the dolutegravir group and 394 in the ritonavir-boosted PI group) were included in the intention-to-treat exposed population. At week 48, a total of 20 participants (5.0%) in the dolutegravir group and 20 (5.1%) in the ritonavir-boosted PI group met the primary end point (difference, -0.04 percentage points; 95% confidence interval, -3.1 to 3.0), a result that met the criterion for noninferiority. No mutations conferring resistance to dolutegravir or the ritonavir-boosted PI were detected at the time of treatment failure. The incidence of treatment-related grade 3 or 4 adverse events was similar in the dolutegravir group and the ritonavir-boosted PI group (5.7% and 6.9%, respectively). CONCLUSIONS: In previously treated patients with viral suppression for whom there were no data regarding the presence of drug-resistance mutations, dolutegravir treatment was noninferior to a regimen containing a ritonavir-boosted PI when the patients were switched from a ritonavir-boosted PI-based regimen. (Funded by ViiV Healthcare; 2SD ClinicalTrials.gov number, NCT04229290.).