IMPORTANCE Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. OBJECTIVE To determine whether hydrocortisone improves outcome for patients with severe COVID-19. DESIGN, SETTING, AND PARTICIPANTS An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. INTERVENTIONS The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). MAIN OUTCOMES AND MEASURES The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned-1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). RESULTS After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR,-1 to 15), 0 (IQR,-1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. CONCLUSIONS AND RELEV...

IMPORTANCEApproximately 25% of patients with early-stage breast cancer who receive (neo)adjuvant chemotherapy experience a recurrence within 5 years. Improvements in therapy are greatly needed.OBJECTIVE To determine if pembrolizumab plus neoadjuvant chemotherapy (NACT) in early-stage breast cancer is likely to be successful in a 300-patient, confirmatory randomized phase 3 neoadjuvant clinical trial. DESIGN, SETTING, AND PARTICIPANTSThe I-SPY2 study is an ongoing open-label, multicenter, adaptively randomized phase 2 platform trial for high-risk, stage II/III breast cancer, evaluating multiple investigational arms in parallel. Standard NACT serves as the common control arm; investigational agent(s) are added to this backbone. Patients with ERBB2 (formerly HER2)-negative breast cancer were eligible for randomization to pembrolizumab between November 2015 and November 2016.INTERVENTIONS Participants were randomized to receive taxane-and anthracycline-based NACT with or without pembrolizumab, followed by definitive surgery. MAIN OUTCOMES AND MEASURESThe primary end point was pathologic complete response (pCR). Secondary end points were residual cancer burden (RCB) and 3-year event-free and distant recurrence-free survival. Investigational arms graduated when demonstrating an 85% predictive probability of success in a hypothetical confirmatory phase 3 trial. RESULTSOf the 250 women included in the final analysis, 181 were randomized to the standard NACT control group (median [range] age, 47 [24.77] years). Sixty-nine women (median [range] age, 50 [27-71] years) were randomized to 4 cycles of pembrolizumab in combination with weekly paclitaxel followed by AC; 40 hormone receptor (HR)-positive and 29 triple-negative. Pembrolizumab graduated in all 3 biomarker signatures studied. Final estimated pCR rates, evaluated in March 2017, were 44% vs 17%, 30% vs 13%, and 60% vs 22% for pembrolizumab vs control in the ERBB2-negative, HR-positive/ERBB2-negative, and triple-negative cohorts, respectively. Pembrolizumab shifted the RCB distribution to a lower disease burden for each cohort evaluated. Adverse events included immune-related endocrinopathies, notably thyroid abnormalities (13.0%) and adrenal insufficiency (8.7%). Achieving a pCR appeared predictive of long-term outcome, where patients with pCR following pembrolizumab plus chemotherapy had high event-free survival rates (93% at 3 years with 2.8 years' median follow-up).CONCLUSIONS AND RELEVANCE When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pCR rates for both HR-positive/ERBB2negative and triple-negative breast cancer, indicating that checkpoint blockade in women with early-stage, high-risk, ERBB2-negative breast cancer is highly likely to succeed in a phase 3 trial. Pembrolizumab was the first of 10 agents to graduate in the HR-positive/ERBB2-negative signature.

Background I-SPY 2 is a phase 2 standing multicenter platform trial designed to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to matching experimental regimens with responding patient subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin (VC). Methods Eligible women had ≥2.5 cm stage II/III breast cancer, categorized into 8 biomarker subtypes based on HER2, hormone-receptor status (HR) and MammaPrint. Patients are adaptively randomized within subtype to better performing regimens compared to standard therapy (control). Regimens are evaluated within 10 signatures, prospectively defined combinations of subtypes. VC plus standard therapy was considered for HER2-negative tumors and therefore evaluated in 3 signatures. The primary endpoint of I-SPY 2 is pathologic complete response (pCR). MR volume changes during treatment inform the likelihood that a patient will achieve pCR. Regimens graduate if and when they have a high (Bayesian) predictive probability of success in a subsequent phase 3 neoadjuvant trial within the graduating signature. Results VC graduated in triple-negative breast cancer with 88% predicted probability of phase 3 success. A total of 72 patients were randomized to VC and 44 to concurrent controls. Respective pCR estimates (95% probability intervals) were 51% (35%–69%) vs 26% (11%–40%). Greater toxicity of VC was manageable. Conclusion The design of I-SPY 2 has the potential to efficiently identify responding tumor subtypes for the various therapies being evaluated. VC added to standard therapy improves pCR rates specifically in triple-negative breast cancer.

Background I-SPY2, a standing, multicenter, adaptive phase 2 neoadjuvant trial ongoing in high-risk clinical stage II/III breast cancer, is designed to evaluate multiple, novel experimental agents added to standard chemotherapy for their ability to improve the rate of pathologic complete response (pCR). Experimental therapies are compared against a common control arm. We report efficacy for the tyrosine kinase inhibitor neratinib. Methods Eligible women had ≥2.5 cm stage II/III breast cancer, categorized into 8 biomarker subtypes based on HER2, hormone-receptor status (HR), and MammaPrint. Neratinib was evaluated for 10 signatures (prospectively defined subtype combinations), with primary endpoint pCR. MR volume changes inform likelihood of pCR for each patient prior to surgery. Adaptive assignment to experimental arms within disease subtype was based on current Bayesian probabilities of superiority over control. Accrual to experimental arm stop at any time for futility or graduation within a particular signature based on Bayesian predictive probability of success in a confirmatory trial. The maximum sample size in any experimental arm is 120 patients, Results With 115 patients and 78 concurrently randomized controls, neratinib graduated in the HER2+/HR− signature, with mean pCR rate 56% (95% PI: 37 to 73%) vs 33% for controls (11 to 54%). Final predictive probability of success, updated when all pathology data were available, was 79%. Conclusion Adaptive, multi-armed trials can efficiently identify responding tumor subtypes. Neratinib added to standard therapy is highly likely to improve pCR rates in HER2+/HR2212; breast cancer. Confirmation in I-SPY 3, a phase 3 neoadjuvant registration trial, is planned.

Writing Committee for the REMAP-CAP Investigators IMPORTANCE The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive.OBJECTIVE To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTSThe ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONSThe immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURESThe primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, −1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. RESULTS Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11...