COVID-19 vaccination, from first dose to booster: New insights into the frequency of most common systemic adverse events and possible booster nocebo effects based on a systematic review

Background: Based on placebo data, it has been recently demonstrated that the frequencies of most common adverse events (AEs) of COVID-19 vaccination are overestimated due to negative expectation bias of vaccine recipients (nocebo effect). Since booster studies lack comparators, estimating the extent of the nocebo effect is difficult. We aimed to overcome this obstacle through a systematic comparison of most common AE frequencies across vaccine doses (first, second, booster), age groups, and vaccine vs. placebo arms. Methods: We systematically assessed systemic AEs in approved COVID-19 vaccines according to the PRISMA guidelines. All documents regarding COVID-19 vaccines with a booster dose authorized by the FDA (cutoff date 19 November 2021) were systematically searched on PubMed and the FDA website. Solicited systemic AEs from all documents supporting approval/authorization were collected. After standardization of doses and age groups, AE frequencies were compared between vaccine and placebo. Findings: Two trials were identified for BNT162b2 (n=21,785 participants), two for mRNA-1273 (n=22,324), and one for Ad26.COV2.S (n=4,085). Fever cases dropped to about half with the booster dose in all vaccines, whereas all other systemic AE frequencies were similar to the preceding dose. Almost no fever cases occurred with placebo (first/second dose); all other systemic AEs occurred at high frequencies. After subtracting placebo arm values from vaccine values, the frequencies for the various AEs were roughly comparable within each dose for each vaccine. Interpretation: Fever is the only solicited systemic AE that can be assessed objectively. It occurs about 50% less often with the booster than with the preceding dose. This may indirectly indicate a considerable overestimation of systemic AEs in the case of booster vaccinations and a pronounced nocebo effect. The nocebo effect appears to substantially contribute to the differences in the frequencies of the various systemic AEs.

Updated Safety and Efficacy Results of Phase 1 Study of Olverembatinib (HQP1351), a Novel Third-Generation BCR-ABL Tyrosine Kinase Inhibitor (TKI), in Patients with TKI-Resistant Chronic Myeloid Leukemia (CML)

Background: Management of CML using TKIs is often constrained by treatment resistance, which portends a poor prognosis. Treatment failure may be due to therapeutic resistance (BCR-ABL1 mutation-dependent or independent), intolerance, and/or suboptimal adherence. The BCR-ABL1 T315I ("gatekeeper") genotype is insensitive to first- and second-generation TKIs, while compound mutations complicate management with all TKIs (including third-generation TKI ponatinib). HQP1351 (olverembatinib) is a novel, third-generation, orally active BCR-ABL1 TKI with evidence of antitumor activity against CML regardless of genotype (Ren X et al. Med Chem 2013;56:879-94) and a preliminary favorable safety profile in clinical trials (Jiang Q et al. Blood 2020;136:50-1). Methods: This Chinese, open label, multicenter, phase 1 trial evaluated the safety and efficacy of olverembatinib in adults with CML in chronic phase (CML-CP) or accelerated phase (CML-AP). Eligible patients have CML-CP or CML-AP that is resistant or intolerant to first- or second-generation TKIs. Patients with severe cardiovascular diseases, hypertension, and pulmonary arterial hypertension were excluded. Olverembatinib is orally administered once every other day in 28-day cycles at 11 dose cohorts ranging from 1 to 60 mg. This study reports data on patients with long-term follow-up. Results: From October 26, 2016, through February 2, 2021 (data cutoff date), 101 patients with CP-CML (n = 86) and AP-CML (n = 15) were enrolled and treated with olverembatinib. Seventy-one (70.3%) patients were male, the median age was 40 (range, 20-64) years, and median (range) interval from diagnosis to initial olverembatinib treatment was 6.0 (0.3-15.2) years. Eighty-four (83.2%) patients received ≥ 2 prior lines of TKI-therapy, and 63 (62.4%) harbored T315I mutation. At baseline, compound mutations were detected in 11 (10.9%) patients, of whom 7 (63.6%) had the BCR-ABL1 T315Igenotype. A total of 20 (19.8%) patients had 2 (n = 13) or ≥ 3 (n = 7) mutations. The median follow-up was 30.8 (1.2-51.8) months. As of the data cutoff date, 81 (80.2%) of 101 patients continued on treatment and 20 (14 CP-CML and 6 AP-CML) discontinued because of disease progression, intolerance, or occurrence of a secondary cancer. The cumulative median (range) drug exposure was 13,635 (1,650-20,975) mg. Of 101 patients, 18 (17.8%) were treated for > 3 years and 5 (5%) for > 4 years. Of evaluable patients without baseline responses, 97.0% had complete hematologic responses (CHR), 62.1% complete cytogenetic responses (CCyR), and 51.0% major molecular responses (MMR). Most evaluable patients with T315I mutations experienced 100% for CHR, 83.7% for MCyR, and 71.2% for MMR among patients in CP-CML, as well as 80.0% for CHR and 54.5% each for MCyR and MMR in AP-CML. At 36 months, the PFS rate (95% CI) was 96.3% (89.1%-98.8%) in patients with CP-CML and 71.4% (40.6%‒88.2%) in those with AP-CML. Treatment responses were durable and unaffected by baseline BCR-ABL1 mutational status. Corresponding values in patients with > 4 years of treatment were 100% (CHR), 80% (CCyR), and 60% (MMR). The mean (95% confidence interval) PFS rate was 100% (100%-100%) at 36 months, 100% at 48 months, and not reached (NR-NR) at 60 months. Most treatment-related adverse events were grade 1 or 2. The most frequent nonhematologic adverse event was (mostly grade 1 or 2) skin hyperpigmentation (86.1%). Grade ≥ 3 nonhematologic AEs included hypertriglyceridemia (10.9%), pyrexia (6.9%), and proteinuria (5.0%). The most common hematologic treatment-related adverse event was thrombocytopenia in 78 (77.2%) patients, including 52 (51.5% of total population) with grade ≥ 3 and 6 (5.9%) with serious adverse events. Leukopenia was grade ≥ 3 in 21 (20.8%) patients but not serious, while anemia was grade 3 or higher in 16 (15.8%) patients and serious in 4 (4.0%). Conclusions: In patients with TKI-resistant CML-CP or CML-AP and long-term treatment, olverembatinib was efficacious and well tolerated. Internal study identifier HQP1351-SJ002. Figure 1 Figure 1. Disclosures Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Niu: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Men: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Wang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

Phase II Trial of Eprenetapopt (APR-246) in Combination with Azacitidine (AZA) As Maintenance Therapy for TP53 Mutated AML or MDS Following Allogeneic Stem Cell Transplantation (SCT)

Background Mutations in the tumor suppressor gene TP53 are found in up to 20% of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Allogeneic hematopoietic SCT remains the only potentially curative therapy however outcomes remain poor, with a 1-year relapse-free survival (RFS) of ~30% and median overall survival (OS) of ~8 months. Prior data on post-SCT maintenance therapies, including AZA, have failed to demonstrate improved post-SCT outcomes. Eprenetapopt, a small molecule p53 stabilizer, targets cellular redox balance resulting in tumor cell apoptosis and ferroptosis as well as immune modulation of the tumor microenvironment. Pre-clinical data demonstrates synergistic myeloid cell cytotoxicity in vitro and in vivo AML burden reduction when eprenetapopt is combined with AZA. Additionally, the known tolerability of this combination in AML/MDS patients makes it an attractive maintenance strategy. Methods This is a multi-center, open label, Phase II clinical trial to assess the safety and efficacy of eprenetapopt in combination with AZA as maintenance therapy after SCT for patients with TP53 mutant AML and MDS. Patients with MDS and AML with a known TP53 mutation were prescreened prior to SCT and protocol eligibility was confirmed post-SCT. Treatment consisted of up to 12 cycles of eprenetapopt 3.7 g/day Days 1-4 with AZA 36 mg/m 2/day IV/SC on Days 1-5 every 28 days. The primary objectives of this study are to assess RFS and the safety and tolerability of the combination. Additional endpoints include OS, time to progression (TTP), non-relapse mortality (NRM) and cumulative incidence of acute and chronic graft-versus-host disease (GVHD). Results The study enrolled a total of 33 patients (19 MDS, 14 AML) for active therapy. Demographics across all patients included median age 65 years (range: 40-74), 64% males, and Karnofsky performance status of ≥ 80 in 79%. The majority (76%) received a reduced intensity conditioning regimen. At initial diagnosis, 97% (32) had TP53 mutations, 9% (3) had >1 TP53 mutation, 82% (27) had complex cytogenetics (>=3), 45% (15) had chromosome (chr) 17, 76% (25) had chr 5, and 45% (15) had chr 7 abnormalities. Among 25 patients with available molecular data from a pre-SCT sample, 22 (88%) patients had a residual detectable TP53 gene mutation, 8 (36%) had > 1 TP53 mutation, and 9 (36%) patients had non-TP53 gene mutations: ASXL1 (2 ), JAK2 (4), DNMT3A (3), IDH2 (2), IDH1 (2), NRAS (1) and SF3B1 (1). As of the data cutoff date of 22 June 2021, patients completed a median of 7 cycles (1,12) of study treatment with 6 patients (18.2%) remaining on study treatment. The primary reasons for study treatment discontinuation among 27 patients, were completion of 12 cycles of treatment (9) and disease relapse (9). With median duration of RFS follow up of 413 days the median RFS was 368 days [95% CI (233-not evaluable)] and the 1-year RFS was 58%. With median duration of OS follow up of 429 days the median OS was 586 days [95% CI (369-not evaluable)] and 1-year OS 79%. All-grade treatment emergent adverse events (TEAEs) occurring in ≥20% of patients included nausea (61%), platelet count decreased (49%), vomiting (46%), anemia, dizziness, and white blood cell count decreased (39% each), fatigue (36%), diarrhea and tremor (33% each), cough, neutrophil count decreased, pruritus, and pyrexia (24% each), abdominal pain, constipation, decreased appetite, headache and hypocalcemia (21% each). Grade ≥3 TEAEs in ≥10% of patients were platelet count decreased (36%), white blood cell count decreased (33%), anemia (27%), neutrophil count decreased (24%), thrombocytopenia and hypertension (12% each). SAEs in ≥2 patients were pyrexia (12%), febrile neutropenia and dyspnea (6% each). Two patients (6%) experienced TEAEs leading to discontinuation of study treatment. Acute and chronic GVHD events of any grade were reported in 12% and 30% of patients, respectively. Conclusions Post-SCT maintenance therapy with eprenetapopt in combination with AZA was safe and tolerable with favorable results in patients with TP53 mutant MDS and AML, with 9 patients completing 12 cycles of therapy at the data cutoff date and the majority of reported TEAEs comprising known complications of high-risk MDS and AML patients in the post-SCT period. In addition, the observed RFS and OS data are highly encouraging compared to the historical outcomes for this high-risk group of patients with unmet medical need. Disclosures Mishra: Novartis: Research Funding. DeZern: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees. Byrne: Karyopharm: Research Funding. Chen: Gamida: Consultancy; Incyte: Consultancy. Gallacher: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wennborg: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kaylor Hickman: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Attar: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Fernandez: Incyte: Honoraria. OffLabel Disclosure: The presentations includes the use of experimental agent eprenetapopt (APR-246) and the agent azacitidine in the post-transplant maintenance setting.

A Novel and Successful Patient or Donor-Derived CD7-Targeted CAR T-Cell Therapy for Relapsed or Refractory T-Cell Lymphoblastic Lymphoma (R/R T-LBL)

Background T-cell lymphoblastic lymphoma is an aggressive hematological malignancy, often presenting with bulky mediastinal masses or diffuse extramedullary disease (EMD). There is evidence that T-LBL differs in various aspects from T-cell acute lymphoblastic leukemia in addition to differences in clinical presentation of diseases. To date, there are only a few clinical case reports of CAR-T therapy for T-LBL. Here, we explored the efficacy and safety of CD7-targeted CAR-T cells (CD7CAR) for R/R T-LBL in a phase I clinical trial (NCT04916860). Methods Eligible R/R T-LBL patients were enrolled between November 2020 and May 2021. Peripheral blood (PB) mononuclear cells were collected from either the donor (n=1) or patients (n=7) by leukapheresis. The CD7-CAR gene was obtained by gene synthesis and then ligated into a lentiviral vector by molecular cloning. We developed second-generation CAR-T cells with an intracellular co-stimulatory domain of 4-1BB and CD3ζ targeting CD7. Intravenous fludarabine (30 mg/m 2/d) and cyclophosphamide (300 mg/m 2/d) were given to all patients on Day -5 to Day -3 prior to CD7CAR infusion. Results Patient characteristics are summarized in Table 1. Eight R/R T-LBL patients were enrolled with a median age of 37 years (14-47 years) and a median of 5 prior lines of therapies (2-10 lines). Two patients had a history of central nervous system involvement. Two patients relapsed from a previous allogenic (N=1) or autologous (N=1) hematopoietic stem cell transplantation (HSCT). Four patients expressed high-risk genotypes including TP53, EZH2 and RUNX1. At enrollment, 7 patients had EMD relapse (diffuse involvement, N=5; bulky mediastinal masses, N=2). One patient had no EMD involvement at enrollment due to a prior palliative mediastinal radiotherapy, but relapsed with bone marrow (BM) blasts up to 87.27%. A total of 5/8 patients had BM blasts at enrollment with median BM blasts of 17%. Both patient- and donor-derived CD7CAR-T cells were successfully generated with a transfection efficiency of 86.55% (27%-98%). A single dose of CD7CAR-T cells was infused to patients at low dose (5x10 5 cells/kg, N=1), medium dose (1x10 6 cells/kg, N=6) or high dose (2x10 6 cells/kg, N=1). The median follow-up time was of 93 days (55-166 days) by July 18, 2021, the cutoff date. Following CD7CAR infusion, 5/5 patients who had prior BM blasts achieved minimal residual disease negative (MRD-) complete remission with incomplete hematologic recovery (CRi) on Day 28, among whom 3 had already achieved MRD- CRi on Day 14. The 3 patients who did not have BM blasts prior to CAR-T infusion maintained zero BM blasts post infusion. Of the 7 patients who had EMD involvements, 4 achieved EMD CR on Day 28, and 1 on Day 51. Of the 2 patients who had bulky mediastinal masses (~7 or 6 cm), 1 had partial response and 1 had stable disease on Day 28, respectively. Of all patients, 6 subsequently underwent allo-HSCT following CD7CAR-T infusion with a median time of 54 days (42-56 days), without relapse or progression. One patient with an allo-HSCT prior to CD7CAR infusion died after receiving a second haploidentical allo-HSCT due to acute graft-versus-host disease. The other 2 patients who did not receive a transplant were on Day 55 and 73 post CD7CAR infusion with ongoing remission by the cutoff date. Mild cytokine release syndrome (CRS, ≤Grade 2) was observed in 7/8 patients. Only 1/8 patient had Grade 3 CRS and Grade 1 neurotoxicity. The median onset of CRS was 1 day post infusion (0-15 days) with a median duration of 16 days (5-19 days). CD7CAR expansion in vivo occurred as early as 3.5 days (0-11 days) post infusion and reached a median peak of 2.07x10 5 copies/ug DNA (0.75-5.36 x10 5 copies/ug DNA) at a median of 19 days (13-28 days), and was still detectable up to the last follow-up, with a median duration of 50 days (26-120 days), as measured by qPCR (Figure.1). Conclusion Our clinical trial showed that CD7CAR-T cells derived either from the patients or the donor have a high initial efficacy and a good safety profile in R/R T-LBL patients. Initial high CR could be achieved both intramedullary and extramedullary in the majority of patients, even among those who harbored with high-risk features or had diffuse extramedullary lesions. However, patients with bulky mediastinal masses may require more than one-month time to achieve remission. Long-term observation and more patients are needed to further evaluate the safety and efficacy of CD7CAR. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

354 Lenvatinib and pembrolizumab in advanced endometrial carcinoma (EC): long-term efficacy and safety update from a phase 1b/2 study

BackgroundLenvatinib is a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT. Pembrolizumab is an anti-programmed death-1 monoclonal antibody. We previously reported results from a cohort of 108 patients with metastatic EC (data cutoff date, January 10, 2019) who received lenvatinib + pembrolizumab as part of an ongoing multicenter, open-label, phase 1b/2 study evaluating the combination treatment in patients with selected solid tumors (NCT02501096). Lenvatinib + pembrolizumab showed a tolerable safety profile and promising antitumor activity per immune-related (ir) Response Evaluation Criteria In Solid Tumors (RECIST) by investigator assessment, including an objective response rate (ORR) of 38.9% (95% confidence interval [CI], 29.7–48.7), median progression-free survival (PFS) of 7.4 months (95% CI, 5.3–8.7), and median overall survival (OS) of 16.7 months (95% CI, 15.0-not estimable).1 Here we present updated efficacy and safety data (data cutoff date: August 18, 2020).MethodsPatients included in the EC cohort had histologically confirmed, measurable metastatic EC and had received ≤2 prior chemotherapies (unless discussed with the sponsor). Patients received lenvatinib (20 mg orally once daily) and pembrolizumab (200 mg intravenously once every 3 weeks). The phase 2 efficacy endpoints included ORR, PFS, OS, and duration of response. Tumor assessments for primary and secondary endpoints were evaluated by investigators per irRECIST.ResultsThe 108 patients from the key efficacy analysis set for the previously reported results were all included in these updated analyses. Median follow-up duration for the study was 34.7 months. Efficacy outcomes are summarized in table 1. Treatment-related adverse events (TRAEs) occurred in 104 (96%) patients (94 [87%] grade ≤3, 10 [9%] grade ≥4). TRAEs led to study-drug interruption of 1 or both drugs in 80 (74.1%) patients and dose reductions of lenvatinib in 73 (67.6%) patients; 23 (21.3%) patients discontinued 1 or both drugs due to a TRAE. The most common grade ≥3 TRAEs were hypertension (33.3%), lipase increased (9.3%), fatigue (8.3%), and diarrhea (7.4%).Abstract 354 Table 1ConclusionsWith extended follow-up, our updated efficacy analysis continued to show clinical benefit in patients with metastatic EC who received lenvatinib + pembrolizumab. Moreover, the combination had a manageable safety profile that was generally consistent with the established safety profiles of the individual monotherapies. No new safety signals were detected. A phase 3 study of lenvatinib + pembrolizumab versus treatment of physician’s choice in advanced endometrial cancer further supports the lasting clinical benefits observed in our study.2Trial Registration www.clinicaltrials.gov NCT02501096ReferencesMakker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol 2020;38(26):2981–2992.Makker V, Colombo N, Casado Herráez A, et al. A multicenter, open-label, randomized, phase 3 study to compare Ethics ApprovalThis study was approved by the following ethics committees/institutional review boards (IRBs): Oregon Health & Sciences University IRB, IntegReview IRB, Memorial Sloan Kettering Cancer Center IRB, University of Pennsylvania Office of Regulatory Affairs IRB, Dana-Farber Cancer Institute IRB, The University of Chicago Biological Sciences Division IRB, University of Texas MD Anderson Cancer Center IRB, Western IRB, Quorum Review IRB, US Oncology, Inc. IRB, CEIm - Comité de Ética de la Investigación con Medicamentos, Regional Komite for Medisinsk og Helsefagli Forskningsetikk, and REC - Regional Committees for Medical and Health Research Ethics. All participants gave informed consent before taking part in this study.ConsentNo identifying information is contained in this abstract so no permission from participants is considered necessary.

Evaluating changes in “good safety monitoring” for cancer clinical trial participants during the COVID-19 pandemic.

217 Background: Comprehensive and frequent safety monitoring is an essential component of clinical trial conduct to accurately characterize potential toxicities of a study drug and to minimize potential harm to study participants. The COVID-19 pandemic substantially impacted the delivery of cancer care with reduced frequency of overall and in-person visits. We hypothesized that reporting of serious adverse events (SAEs) occurring on clinical trials may have been impacted by these care delivery changes. The current study evaluated pandemic-related changes in the frequency of safety monitoring for cancer patients (pts) enrolled on a clinical trial and identified predictors of SAE reporting before and during the pandemic. Methods: This study included all adult cancer pts enrolled in interventional therapeutic clinical trials at an academic cancer center between 1/1/2019 and 12/30/2020. In this analysis, the "pre-pandemic" period was defined as the time between 1/1/19 and 3/14/20, and the pandemic period between 3/15/20 and the data cutoff date of 12/30/2020. SAE was defined as a grade 3 or grade 4 adverse event (AE) as reported by the trial. Demographic characteristics of pts, visit type (virtual vs in-person), and frequency of SAE reporting were summarized pre-pandemic and during the pandemic. A multivariate logistic regression model was employed to identify predictors of SAE reporting, with the outcome defined as report of at least one SAE from the time pts went on study until the data cutoff date. Covariates included age, gender, race (white vs. non-white), having at least one virtual visit, and enrollment on a trial before versus during the pandemic. Results: This study included 190 pts; 138 (73%) enrolled on trial pre-pandemic and 52 (27%) enrolled during the pandemic. During-pandemic participants were more likely to be older than pts enrolled pre-pandemic, but otherwise the groups were similar in terms of race and gender. Overall, 78 pts (41%) reported an SAE. Among pre-pandemic enrollees, 50% reported at least one SAE, compared to 17% among during-pandemic enrollees. In the multivariate logistic regression model, only enrolling on trial pre-pandemic was associated with a higher likelihood of reporting at least one SAE. Visit type (virtual vs. in-person) was not recorded in over half of during-pandemic patient encounters. Conclusions: There was a significant decline in frequency of SAE reporting during the COVID-19 pandemic. While having at least one virtual visit was not a significant predictor of SAE reporting in the multivariate regression model, our analysis may underrepresent the association of virtual visits and SAE reporting. As the number of virtual visits is expected to stay high post-pandemic, further work is needed to characterize the association of virtual visits and SAE reporting to ensure ongoing adequate safety monitoring for clinical trial patients.

Does Career Risk Deter Potential Entrepreneurs?

Do potential entrepreneurs remain in wage employment because of concerns that they will face worse job opportunities should their entrepreneurial ventures fail? Using a Canadian reform that extends job-protected leave to one year for women giving birth after a cutoff date, we study whether the option to return to a previous job increases entrepreneurship. A regression discontinuity design reveals that a longer job-protected leave increases entrepreneurship by 1.9 percentage points. These entrepreneurs start incorporated businesses that hire employees, in industries in which experimentation before entry has low costs and high benefits.

Symptomatology associated with the diffusion of the SARS-CoV-2 Lambda variant in Peru: An infodemiologic analysis

The SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) Lambda variant rapidly diffused across Peru following its identification in December 2020, and had now spread worldwide. In this study, we investigated infodemiologic trends in symptomatology associated with the Coronavirus Disease 2019 (COVID-19) following the spread of SARS-CoV-2 Lambda variant in Peru, enabling infodemiologic surveillance of SARS-CoV-2 in regions with high circulation of this new variant. Weekly Google Trends scores were obtained for key symptom keywords between March 1st, 2020 and July 4th, 2021, whilst case count data were obtained from Peruvian Ministry of Health. Multiple time series linear regression was used to assess trends in each score series, using the week of December 27th as cutoff for emergence of the Lambda variant. The significance of such trends was tested for each time period, before and after the cutoff date. A total 2,075,484 confirmed SARS-CoV-2 infections in Peru in relation to Google Trends data were analyzed. After Lambda variant emergence, searches for diarrhea demonstrated a change from a negative to positive correlation with weekly case counts and anticipated dynamic changes in case counts by 1-5 weeks. Searches for shortness of breath and headache remained consistently positively correlated to weekly case counts before and after Lambda emergence. No changes in searches for other common cold symptoms were observed, while no specific trends were observed for taste loss or smell loss. Diarrhea, headache, and shortness of breath appear to be the most important symptoms for infodemiologic tracking the current outbreak in Peru and other regions with high circulation of SARS-CoV-2 Lambda variant.

Polatuzumab vedotin (Pola) + rituximab (R) + lenalidomide (Len) in patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): Primary analysis of a phase 1b/2 trial.

7512 Background: The combination of Pola-R-Len may enhance anti-tumor response in R/R DLBCL. We report the primary analysis of the R/R DLBCL cohort in a Phase 1b/2 study (GO29834; NCT02600897). Methods: Pts received induction with 6 x 28-Day (D) cycles (C) of: Pola 1.8mg/kg intravenous (IV; C1−6: D1); R 375mg/m2 IV (C1−6: D1) and oral Len 10–20mg (dose escalation) or recommended Phase 2 dose (RP2D) daily on D1–21. Pts with a response at end of induction (EOI) received 6 months (mo) consolidation with R 375mg/m2 (D1 every 2 mo) and Len 10mg (D1–21 monthly). Primary endpoints were safety/tolerability and positron emission tomography (PET)-complete response (CR) rate at EOI by independent review committee (IRC) by modified Lugano criteria. Results: At primary analysis (Sep 08, 2020), 57 pts were enrolled. Median age was 71 years (range 28–92); male (67%); Ann Arbor Stage III–IV (86%); International Prognostic Index 3–5 (60%); median 2 prior therapies; prior bone marrow transplant (11%); prior CAR-T therapy (5%); primary refractory (49%) and refractory to last therapy (65%). Grade 3–4 adverse events (AEs) were experienced by 75% of pts, most commonly, neutropenia (58%), thrombocytopenia (14%), infections (14%) and anemia (11%). AEs led to Len dose reduction in 25% and interruption in 63% of pts. One Grade 5 treatment-related AE (neutropenic sepsis) was reported. In total, 49 pts were treated at RP2D (Pola 1.8mg/kg + Len 20mg). IRC PET-CR rate at EOI was 29% (Table). A best overall response (BOR) assessed by investigator (INV) was seen in 36/49 (74%) pts with 17/49 (35%) pts achieving a CR; of these, 14/17 (82%) remain in remission at the cutoff date. Median duration of response (DOR) was 8.1 mo (95% confidence interval [CI]: 4.7–not evaluable [NE]). After a median follow-up of 9.7 mo, median progression-free survival (PFS) and overall survival (OS) were 6.3 mo (95% CI: 4.5–9.7) and 10.9 mo (95% CI: 7.4–NE), respectively. Conclusions: Our study of the novel triplet combination, Pola-R-Len, demonstrates a tolerable safety profile. This first efficacy report of Pola-R-Len shows promising activity in a difficult-to-treat R/R DLBCL population, particularly in pts achieving CR, a large proportion of whom remain in remission at the cutoff date. Further evaluation of Pola-R-Len and the impact of consolidation therapy is warranted to address the significant unmet need in this patient population. Clinical trial information: NCT02600897. [Table: see text]