bluuebunny/crossref_metadata_2025 huggingface dataset:
Toripalimab combined with chemoradiotherapy for patients with locally advanced cervical squamous cell carcinoma.
Authors: Ou Dan , Xu Haoping
Published: June 2022

5538

Background: To assess the safety and efficacy of toripalimab combined with chemoradiotherapy for locally advanced cervical squamous cell carcinoma (Chinese Clinical Trial Registry number, ChiCTR2000032879). Methods: Twenty-two locally advanced cervical cancer patients, regardless of programmed death ligand-1 status, received toripalimab treatment combined with concurrent chemoradiotherapy. Concurrent chemoradiotherapy(CCRT) includes cisplatin (40 mg/m2, once a week for 5 weeks), radiotherapy (external irradiation 45-50.4Gy/25-28Fx, 5 fractions a week, followed by brachytherapy 24-30Gy/3-5Fx) and toripalimab (240mg on days 1, 22 and 43). The primary end-point was safety and feasibility. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), overall survival (OS). Results: The median age was 55 years old (range, 42 to 72 years old), with 2 patients in FIGO stage II, 15 patients in stage IIIC, and 5 patients in stage IVA. All patients have received CCRT successfully. Grade III and higher adverse events (AEs) were observed in 10 patients (10/22, 45.5%), and no patient had a grade V AE. The most frequent grade III AE was leukopenia (8/22, 36.4%). The most common immunotherapy-related adverse reaction was hypothyroidism (2/22, 9.1%). The 3-month ORR rate was 95.5%. At data cutoff (Jan 31, 2022), the median follow-up was 10 months (range, 3.30 to 16.73 months). One patient developed multiple metastases 3 months after treatment, and 1 patient developed lung metastasis 6 months after treatment. The ORR was 100%, while the PFS rate was 90.1%, and the OS rate was 95.5%. Conclusions: Toripalimab combined with concurrent chemoradiotherapy demonstrated a manageable safety profile and promising anti-tumor activity in patients with locally advanced cervical cancer, thus might represent a novel treatment option for this patient population. Longer follow-up results and further phase II/III studies are expected. Clinical trial information: ChiCTR2000032879.
Racial differences in the mutational landscape of serous endometrial cancer.
Authors: Schink Julian C. , Garg Ruchi , Buttin Barbara , Elvin Julia Andrea , Godbee Natalie , Moran Amber , Doctor Vicki , Tan Bradford A. , Farley John H. , Markman Maurie
Published: June 2022

5600

Background: Tumor comprehensive genomic profiling (CGP) identifying genomic alterations (GA) that have diagnostic, prognostic and are potentially therapeutically targetable is essential to precision oncology. 2022 NCCN Uterine Neoplasm guidelines recommend tumor genetic evaluation as part of initial evaluation. As racial disparities in endometrial cancer outcomes have been widely reported, we analyzed our CGP results from a large series of serous endometrial cancer patients treated in a nationwide cancer network to identify GA differences that may contribute to worse prognosis and help inform better therapy selection. Methods: 86 Pts with serous endometrial underwent hybrid-capture based CGP for up to 324 cancer-related genes of archival tumor tissue or 62 genes on circulating tumor DNA ordered during clinical care for treatment decision-making between 01-2013 to 07-2021. Clinically relevant genomic alterations (CRGA) were defined as associated with targeted therapies or mechanism-driven clinical trials. Statistical analysis performed with Fisher Exact test comparing Black and White women. Results: Median age was 63 years (range, 38-85), 37% were White, 58% were Black and 5% were Asian. GA were identified in 94% (81/86) of these patients. TP 53 mutations which is characteristic of serous cancer were present in 80 of 86 patients (93%). GA predicted to activate PI3-Kinase pathway signaling ( PIK3CA, PIK3R1, PTEN) were significantly more common in White women occurring in 13 of 32 (41%), compared with 8 of 50 (16%) of Black women (p. < 0.02). An important, but not statistically significant trend of greater percentage of CCNE1 amplification in Black women is also noted, see table below: Mutation frequencies were similar between Black and White women for the following genes: PPP2R1A 23%; MYC 19%; FBXW7 14%; ARID1A 9%. Conclusions: In this 86 patient series of women with Serous Endometrial Cancer we note that PIK3CA mutations, an important resistance factor in anti-HER2 therapy, were significantly more common in White women (41%) compared with Black women (16%) (p. < 0.02) and ERBB2 mutations occurred in 19% of White women and only 10% of Black women. This study cohort also identified a larger percentage of black women with CCNE1 amplification. Increased CCNE1 amplification has been linked to the racial disparities in cancer outcomes and may explain the disparities seen with endometrial cancers.

[Table: see text]
Immune landscape of breast tumors with low and intermediate estrogen receptor (ER) expression.
Authors: Voorwerk Leonie , Horlings Hugo M. , Sanders Joyce , Keusters Milou S. , Cornelissen Sten , Sonke Gabe S. , Linn Sabine C. , Kok Marleen
Published: June 2022

566

Background: Immune checkpoint blockade (ICB) is currently only approved for patients with triple-negative breast cancer (TNBC). However, the cut-off used for ER expression (<1% and in some countries <10%) has been developed as a biomarker for endocrine treatment response and not for selection for likelihood of response to ICB. While stromal tumor-infiltrating lymphocytes (sTILs) and PD-L1 expression are higher in TNBC compared to ER-positive tumors, the distribution of these and other key immune parameters in tumors with very low (1-9%), low (10-50%), intermediate (51-99%) and high (100%) ER levels is unknown. Methods: We collected a consecutive series of treatment-naïve tumor blocks of ER+/HER2- breast tumors diagnosed between 2010 and 2019. All available tumor blocks were used from the groups with ER expression between 1-9% and 10-50%. For the other groups, we randomly selected tumor blocks aiming for similar group sizes. This resulted in the following subgroups: ER 0% (n=46), 1-9% (n=17), 10-50% (n=22), 51-99% (n=37) and 100% (n=51). sTILs were scored using H&E slides. Immunohistochemistry was performed for CD8 and PD-L1 (22C3, scored on immune cells, cut-off ≥1%). Gene expression analysis was performed using the NanoString nCounter Breast Cancer 360 panel. Results: We found the highest levels of sTILs and stromal CD8+ cells in tumors with ER0% with comparable levels in tumors with ER1-9% and ER10-50% (Table). The proportion of PD-L1 positive tumors was 86% in tumors with ER0%, 81% in tumors with ER1-9%, 76% in tumors with ER 10-50% and 59% and 50% in tumors with ER51-99% and 100% respectively. As expected, a higher differentiation grade correlated with lower levels of ER expression. Differential gene expression demonstrated that expression of immune-related signatures, such as IDO1, antigen presenting machinery, CD8+ T cells and IFNγ, was comparable in tumors with ER1-50% as compared to ER0%, but statistically significantly higher as compared to tumors with ER100%. Conclusions: Our data suggest that breast tumors with low levels of ER expression (1-9%, 10-50%) comprise a separate entity within ER-positive breast cancer regarding their immune landscape. Here we show that not only tumors with very low ER levels (1-9%) mimic TNBC in terms of immune landscape but also that tumors with low ER levels (10-50%) might be more likely to respond to ICB than tumors with high levels of ER expression. [Table: see text]
Incidental pulmonary nodules, lung cancer screening, and lung cancer in the Medicare population.
Authors: Osarogiagbon Raymond U. , Miller Eric A , Faris Nicholas , Pinsky Paul F
Published: June 2022

6536

Background: Low-dose CT lung cancer screening (LDCT) saves lives, but only 5%-10% of eligible persons in the US have participated. Management of indeterminate pulmonary nodules (IPNs) identified on CT scans may also reduce lung cancer mortality. We assessed the frequency of IPNs, estimated cumulative lung cancer rates following IPNs, and compared characteristics of lung cancers diagnosed following IPNs versus LDCT screens. Methods: We defined 2 cohorts in the SEER-Medicare database: persons with 12+ months of Medicare Part A&B coverage during 2014-2019 comprised the 5% sample cohort; persons in SEER-Medicare diagnosed with lung cancer during 2015-2017 with Part A&B coverage for the prior 18-month period comprised the lung cancer cohort. We defined IPNs as chest CTs with ICD-10 codes of R91.1 (solitary pulmonary nodule) or R91.8 (other nonspecific abnormal finding of lung field) on the same date as the CT; we used corresponding ICD-9 codes through September 2015. We classified lung cancer cohort cases by whether they had an LDCT (LDCT group), an IPN without an LDCT screen (IPN-only), or neither (Referent) within 18 months before diagnosis. We compared cancer stage and survival between these groups. Results: Of 627,547 subjects in the 5% sample cohort, 58.6% were women; 85.6% were non-Hispanic White (NH-Whites) and 7.7% non-Hispanic Black (NH-Blacks). Over median 5.0 years follow-up, 26.3% had chest CTs and 12.0% had IPNs. The IPN rate was similar by sex but significantly higher in NH-Whites (12.7%) than NH-Blacks (9.7%). The cumulative lung cancer rate following initial IPNs was 2.27% at two years. Of the 44,194 lung cancer cohort cases (85.8% NH-White, 8.2% NH-Black), 26.9%, 2.9% and 70.2% were in the IPN-only, LDCT, and Referent groups, respectively. NH-Whites comprised a higher proportion of LDCT than of IPN-only cases (90.1% vs. 88.4%), while for NH-Blacks, the reverse was true (5.4% vs. 6.5%). The ratio of LDCT:IPN lung cancer cases was 1:9. Among IPN-only and LDCT group cases, 52.0% and 50.3%, respectively, were localized stage, compared to 21.5% for the Referent group. Among all localized cases, 45.4% and 4.9% were in the IPN-only and LDCT groups, respectively. Comparing 3-year survival between IPN vs LDCT vs Referent groups, respectively: aggregate overall survival rates were 53.5% v 59.2% v 29.2%; aggregate lung cancer-specific survival, 71.1% v 75.3% v 46.6%; overall survival for localized cases, 73.2% v 80.7% v 62.9%; lung cancer-specific survival rates for localized cases, 88.2%, 91.8% and 81.4%. Conclusions: Subjects with IPNs had similar stage distribution and survival as LDCT-screened subjects. Almost half of localized cases had prior IPNs, compared to a < 5% of LDCT-screened cases. IPN programs, by circumventing implementation barriers to LDCT, may expand access to early lung cancer detection, including to African American patients and in places where LDCT coverage is not available.
Changes in cancer-related mortality during the COVID-19 pandemic in the United States.
Authors: Zhao Jingxuan , Han Xuesong , Miller Kimberly , Zheng Zhiyuan , Nogueira Leticia M. , Islami Farhad , Jemal Ahmedin , Yabroff K. Robin
Published: June 2022

6581

Background: The coronavirus disease 2019 (COVID-19) pandemic resulted in delayed medical care that may have led to increased death rates in 2020 among people with medical conditions such as cancer. This study examined changes in cancer-related mortality between 2019 and 2020. Methods: We used the US 2019-2020 Multiple Cause of Death database from the CDC WONDER to identify cancer-related deaths, defined as decedents with invasive or noninvasive cancer as a contributing cause of death (ICD-10 codes: C00-C97 and D00-D09). We compared age-standardized cancer-related annual and monthly mortality rates (per 100,000 person-years and person-months, respectively) in January-December 2020 (pandemic) versus January-December 2019 (pre-pandemic) overall and stratified by rurality and place of death. We calculated the 2020 excess death by comparing the numbers of observed death with the projected death based on age-specific cancer-related death rate from 2015 to 2019. Results: The number of cancer-related deaths was 686 054 in 2020, up from 664 888 in 2019, with an annual increase of 3.2%. Compared to the number of projected deaths for 2020 (666 286), the number of cancer-related excess deaths was 19 768 in 2020. Annual age-standardized cancer-related mortality rate (per 100,000 person-years) continuously decreased from 173.7 in 2015 to 162.1 in 2019, while it increased to 164.1 in 2020 (2020 vs 2019 rate ratio (RR): 1.013, 95% confidence interval (CI): 1.009 - 1.016). The cancer-related monthly mortality rate was higher in April 2020 (RR: 1.032, 95% CI: 1.020 – 1.044) when healthcare capacity was most challenged by the pandemic, subsequently declined in May and June 2020, and higher mortality rates were again observed each month from July to December 2020 compared to 2019. In large metropolitan areas, the largest increase in cancer-related mortality was observed in April 2020, while in non-metropolitan areas, the largest increases occurred from July to December 2020, coinciding with the time-spatial pattern of COVID-19 incidence in the country. Compared to 2019, cancer-related mortality rates were lower from March to December 2020 in medical facilities, hospice facilities, and nursing homes or long-term care settings but higher in decedent's homes. Conclusions: The COVID-19 pandemic led to significant increases in cancer-related deaths in 2020 versus 2019. Ongoing evaluation of the spatial-temporal effects of the pandemic on cancer care and outcomes is warranted, especially in relation to patterns in vaccine uptake and COVID-19 hospitalization rates.[Table: see text]
Cost effectiveness of adjuvant olaparib for BRCA-mutated, early-stage breast cancer.
Authors: Zettler Christie , De Silva Dilanka , Blinder Victoria Susana , Robson Mark E. , Elkin Elena B.
Published: June 2022

6593

Background: An interim analysis of the OlympiA trial found that olaparib given in the adjuvant setting can improve distant disease-free and overall survival for patients with early-stage, BRCA-mutated breast cancer; however, the cost-effectiveness of adjuvant olaparib is unknown. This study aimed to evaluate the cost-effectiveness of adjuvant olaparib in patients with early-stage, BRCA-mutated breast cancer. Methods: We used a decision-analytic model to compare outcomes of treatment with and without one year of oral olaparib after completion of systemic therapy in 42-year-old women with BRCA-mutated, early-stage breast cancer. Olaparib’s effectiveness was based on the OlympiA trial, and other model parameters were identified from the literature. We calibrated the model to reflect the 1-, 2-, and 3-year distant disease-free survival (DDFS) and overall survival (OS) observed in the OlympiA trial, and we assumed that olaparib reduced the risk of distant recurrence only in the first 3 years. Olaparib was estimated to cost $14,523 per month. Average lifetime costs were estimated from a health care system perspective in 2021 $ US, and incremental cost-effectiveness ratios (ICER) were estimated as $ per quality-adjusted life-year (QALY) gained. Costs, life-years, and QALYs were discounted by 3% annually. Results: Simulating the OlympiA trial, DDFS for the olaparib arm was 94.3% at 12 months, 90.0% at 24 months, and 87.5% at 36 months, compared to placebo with DDFS of 90.2%, 83.9%, and 80.4% respectively. Similarly, OS for the olaparib arm was 98.1%, 94.8%, and 92.0% compared to 96.9%, 92.3%, and 88.3% with placebo at 12, 24, and 36 months respectively. In the base case, adjuvant olaparib was associated with a 1.21-year increase in life expectancy and a 1.15-QALY increase at an incremental cost of $131,167 compared to placebo. The resulting ICER was about $114,500/QALY gained. At a willingness-to-pay threshold of USD$150,000/QALY, olaparib was cost effective at its current price. Results were sensitive to assumptions about the effectiveness of olaparib and its impact on quality of life. Conclusions: Adjuvant olaparib is cost-effective for women with early-stage, BRCA-mutated breast cancer at the current price of olaparib in the U.S. and at a willingness-to-pay threshold of $150,000. As such, clinicians and payers should consider adjuvant olaparib as a cost-effective option for this patient population. [Table: see text]
BTX-1188, a first-in-class dual degrader of GSPT1 and IKZF1/3, for treatment of acute myeloid leukemia (AML) and solid tumors.
Authors: Chourasia Aparajita Hoskote , Majeski Hannah , Pasis Angela , Erdman Paul , Oke Ashwini , Hecht David , Lonergan David , Mercurio Frank , Chan Kyle , Thai Dung Luong , Fung Leah
Published: June 2022

7025

Background: BTX-1188 is a first-in-class oral molecular glue that degrades GSPT1 and IKZF1/3 and is currently in phase 1 clinical trials for treatment of hematologic and solid malignancies. Targeted protein degradation of cereblon neosubstrates is clinically validated in the treatment (tx) of hematologic malignancies (Lu 2014, Zou 2020). Methods: Cell viability in BTX-1188-treated cells and patient samples was measured by CellTiter-Glo 2.0 assay (Promega). Substrate degradation and apoptosis profiles were analyzed by immunoblots of protein lysates from cells treated with DMSO or BTX-1188. Vehicle, or 30 or 40 mg/kg IP BTX-1188, was used in athymic nude mice AML xenograft models. Results: BTX-1188 is a rapid, deep, and potent degrader of GSPT1 and IKZF1/3 and inhibitor of Myc in several cancer cell lines (Table). Proteomics and immunoblot analysis of AML cell line, MV-4-11, shows significant degradation of GSPT1 and IKZF1 after 2 h tx with 100 nM BTX-1188 ( P<1x10-5) and 6 h tx with 3 nM BTX-1188 (>90% of GSPT1), respectively, indicating rapid and potent neosubstrate degradation. BTX-1188 also durably degrades GSPT1 where tx with 30 nM for 6 h followed by washout maintains significantly lower levels of GSPT1 and sustained apoptosis for up to 24 h. Owing to IKZF1/3 degradation, BTX-1188 has immunomodulatory properties as seen by inhibition of proinflammatory cytokines (IL-1β, IL-6, TNFα) and induction of IL-2 by LPS and αCD3-stimulated PBMCs, respectively. This approach is expected to improve clinical outcomes and reduce toxicities associated with pure GSPT1 degradation (CC-90009), thus expanding the therapeutic window of BTX-1188. Functionally, BTX-1188 is cytotoxic in various cancer cell lines such as Myc-driven lines (IC50 range: 0.5-10 nM) and primary human AML patient samples (IC50 range: 0.4-1.5 nM), including relapsed/refractory-, cytarabine- and venetoclax-resistant samples. The durability of GSPT1 degradation and sustained apoptosis in response to BTX-1188 tx is further reflected in in vivo efficacy models where daily or intermittent dosing of BTX-1188 results in potent and sustained antitumor activity. Conclusions: These preclinical data show that BTX-1188 is a promising drug candidate for AML and other tumor types. Its immunomodulatory properties owing to IKZF1/3 degradation may prevent systemic inflammatory dose-limiting toxicities associated with pure GSPT1 degradation (Uy 2019). BTX-1188 has entered phase 1 clinical studies for advanced solid tumors and AML. DC50 (nM) or inhibitory concentration (nM) of BTX-1188 at 6 h of Tx. [Table: see text]
Association of frailty with clinical and financial outcomes of allogeneic hematopoietic stem cell transplant.
Authors: Sakowitz Sara , Ng Ayesha , Ebrahimian Shayan , Benharash Peyman , Schiller Gary J.
Published: June 2022

7046

Background: Considered the only curative therapy for many hematological conditions, allogeneic hematopoietic stem cell transplantation (alloHSCT) is increasingly used in older patients. Yet, chronological age alone has been found to be an inaccurate predictor of posttransplant sequelae. More recently, the concept of frailty has emerged as a better marker of physiologic reserve. While formal frailty instruments have not been widely adopted due to their resource intensive nature, we applied a previously-validated coding-based approach to examine the association of frailty with in-hospital outcomes of alloHSCT. Methods: All adults (≥ 18 years) undergoing alloHSCT for hematological malignancies were identified in the 2010-2019 Nationwide Readmissions Database. The previously-validated binary Johns Hopkins Adjusted Clinical Groups indicator was used to classify patients as frail. In this algorithm, the presence of diagnoses across various domains, including malnutrition, dementia, and decubitus ulcer, constitute frailty. Regression models were developed to evaluate the independent association of frailty with in-hospital mortality, periprocedural complications, length of stay, hospitalization costs, and 30-day non-elective readmissions. Results: Of an estimated 48,161 patients, 9.8% were considered frail. Frail patients were not significantly older (51.8 ± 15.0 vs 51.6 ± 14.2, p = 0.685), but had higher Elixhauser scores (2.8 ± 1.3 vs 2.0 ± 1.3, p < 0.001). After adjustment, frailty was associated with increased odds of in-hospital mortality (AOR 2.22; 95% CI 1.68-2.94; P < 0.001), as well as infectious (AOR 1.44, 95% CI 1.18-1.76; P < 0.001) and respiratory (AOR 1.69, 95% CI 1.41-2.02; P < 0.001) complications. Frailty was also associated with greater risk of acute graft-vs-host disease (AOR 1.39, 95% CI 1.12-1.72; P = 0.003) and CMV (AOR 1.72, 95% CI 1.27-2.33; P < 0.001) or invasive fungal infection (AOR 1.49, 95% CI 1.07-2.06; P = 0.017). Further, frailty was linked to increased likelihood of non-home discharge (AOR 1.29, 95% CI 1.03-1.61; P = 0.026), 30-day non-elective readmissions (AOR 1.29, 95% CI 1.11-1.50; P = 0.001), and significant increases in length of stay (+6.05 days, 95% CI 4.41-7.69; P < 0.001) and costs (+$36,660, 95% CI 27,413-45,907; P < 0.001). Conclusions: Among patients undergoing alloHSCT, frailty, as measured by an administrative tool, was independently associated with increased in-hospital mortality, complications and overall resource use. Inclusion of frailty in risk models may better aid benchmarking efforts and inform shared-decision making. [Table: see text]
Bosutinib (BOS) in newly diagnosed chronic myeloid leukemia (CML): Gastrointestinal (GI), liver, effusion, and renal safety characterization in the BFORE trial.
Authors: Cortes Jorge E. , Milojkovic Dragana , Gambacorti-Passerini Carlo , García-Gutierrez Valentin , Mauro Michael J. , Leip Eric , Purcell Simon , Viqueira Andrea , Brümmendorf Tim H.
Published: June 2022

7049

Background: Efficacy and safety of BOS vs imatinib (IMA) in patients (pts) with newly diagnosed chronic phase CML was assessed in the phase 3 BFORE trial. Here we characterize the safety profile of BOS after 5 yrs follow-up, with a focus on GI, liver, effusion and renal treatment-emergent adverse events (TEAEs). Methods: Pts who received ≥1 dose of BOS (n=268) or IMA (n=265) 400 mg/d in BFORE were included. Adverse events (AEs) of special interest were analyzed by selecting prespecified MedDRA terms to generate TEAE clusters. Final database lock: June 12, 2020. Results: Median duration of treatment (Tx) was 55 mo for pts receiving BOS or IMA; respective median (range) dose intensity was 393.6 (39–583) vs 400.0 (189–765) mg/d. Any grade TEAEs occurred in 98.9% and 98.9% of BOS- vs IMA-treated pts. Most common newly occurring TEAEs (any grade) after 12 mos were increased lipase (9.0%) with BOS, and diarrhea (8.3%) with IMA. In BOS- vs IMA-treated pts, 25.4% vs 14.3% had AEs leading to permanent Tx discontinuation; the majority discontinued in yr 1 (14.2% vs 10.6%). Most frequent AEs leading to discontinuation were increased ALT (overall, 4.9%; yr 1, 4.5%) with BOS vs thrombocytopenia (overall, 1.5%; yr 1, 1.5%) with IMA. GI, liver, effusion and renal TEAEs, respectively, occurred in 79.9%, 44.0%, 6.0% and 10.4% (maximum grade 3/4 [G3/4]: 9.0%, 26.9%, 1.1% and 2.2%) of BOS- vs 61.5%, 15.5%, 2.3% and 9.8% (G3/4: 1.1%, 4.2%, 0.4% and 0.8%) IMA-treated pts. One grade 5 renal TEAE occurred in the BOS arm and was not considered related to Tx. Cumulative rates per Tx yr are shown in the Table. Most common GI TEAEs were diarrhea (BOS vs IMA: 75.0% vs 40.4% [G3/4: 9.0% vs 1.1%]) with BOS, and nausea (37.3% vs 42.3% [G3/4: 0% vs 0%]) with IMA. In both arms, the most common liver, effusion and renal TEAEs, respectively, were increased ALT and/or AST (34.0% vs 8.3% [G3/4: 22.0% vs 2.3%]), pleural effusion (5.2% vs 1.9% [G3/4: 0.7% vs 0.4%]) and increased blood creatinine (6.7% vs 8.3% [G3/4: 0.4% vs 0.4%]). GI, liver, effusion and renal TEAEs infrequently led to Tx discontinuation (1.9%, 7.8%, 0.7% and 0.7% vs 1.1%, 0.8%, 0% and 0.4%). Conclusions: The safety profiles of BOS and IMA in BFORE were distinct, with no new safety signals identified after 5 yrs follow-up. Onset of TEAEs occurred primarily during yr 1 (eg, GI and liver), with an increased incidence of some TEAEs (eg, effusion and renal) in later yrs. Discontinuations due to AEs generally occurred early into Tx, with few due to GI, liver, effusion and renal AEs. These safety results support the use of first-line BOS as a standard of care in pts with CP CML. Clinical trial information: NCT02130557. [Table: see text]
A phase 1 study of ADI-001: Anti-CD20 CAR-engineered allogeneic gamma delta (γδ) T cells in adults with B-cell malignancies.
Authors: Neelapu Sattva Swarup , Hamadani Mehdi , Miklos David Bernard , Holmes Houston , Hinkle John , Kennedy-Wilde Jackie , Maller Ori , Weinstein Maggie , Galimi Francesco , Lai Rose , Stevens Don A.
Published: June 2022

7509

Background: ADI-001 is a first-in-class allogeneic gamma delta (γδ) CAR T-cell therapy targeting the B-cell antigen CD20. ADI-001 also has both adaptive and innate cytotoxic effector functions to complement CAR targeting, potentially enhancing efficacy and reducing the possibility of tumor escape due to antigen loss. ADI-001 expresses MHC independent γδ T cell receptors, thus lowering the risk of graft versus host disease (GvHD) without the need for gene-editing. Methods: This phase 1 trial evaluates ADI-001 in adults with relapsed/refractory advanced B-cell lymphoma. Eligibility criteria included presence of measurable lesions, expression of CD20 and ≥ 2 prior systemic therapies. All patients received conditioning therapy with fludarabine and cyclophosphamide. ADI-001 is administered at 3 flat dose levels (DL; DL1:3E7, DL2:1E8, or DL3:3E8 cells) in a 3 + 3 dose-escalation scheme. Dose-limiting toxicities (DLT) were monitored during the initial 28-days post-treatment. Patients who completed the 28-day DLT period were considered evaluable. Treatment-emergent adverse events were graded by CTCAE v5.0, and immune effector cell toxicity assessment and grading were performed per ASTCT criteria. Objective response rates (ORR) were evaluated by independent radiographic review per Lugano 2014 criteria. Results: As of 14 February 2022, eight patients were enrolled and six were evaluable. Of these six patients, 2/6 were female (33%) and the median age was 62 years (range 45-75). The median number of prior therapies was 3.5 (range 2-5) and median IPI score was 3.5 (range 2-4). One patient received prior anti-CD19 CAR T cells therapy with lisocabtagene maraleucel. There were five patients with large B-cell lymphoma and one with mantle cell lymphoma. Among the six evaluable patients, three were treated on DL1 and three on DL2. Most related AEs (78%) were of grade 1/2. There were three AESI: two CRS (one grade 1 and one grade 2) and one grade 1 ICANS, and the only related SAEs were the grade 2 CRS and grade 1 ICANS. There was no reported GvHD and no protocol defined DLT events. At day 28, the ORR based upon PET/CT was 67% (4/6 patients) and the CR rate was 67% (4/6 patients). Both patients with ≥ 3 months post-treatment follow-up remained in CR. Additional data will be presented at the meeting. Conclusions: ADI-001 γδ CAR T cells were well tolerated, with a favorable safety profile and encouraging preliminary efficacy. Patients who achieved CR at day 28 appeared to be disease free during further follow-up at month-3. Clinical trial information: NCT04735471.
Phase 1/2 study of anbalcabtagene autoleucel, novel anti-CD19 CAR-T cell therapy with dual silencing of PD-1 and TIGIT in relapsed or refractory large B-cell lymphoma.
Authors: Kim Won Seog , Kim Seok Jin , Yoon Sangeun , Kim Jong Ran
Published: June 2022

7522

Background: Anbal-cel is a novel 2nd generation autologous CD19 CAR-T cell therapy which has been knock-downed for PD-1 and TIGIT using OVIS platform. Anbal-cel demonstrated the eradication of CD19 positive tumor cells in vitro and in vivo better than conventional CD19 CAR-T cells. The knock-down of PD-1 and TIGIT at CD19 CAR-T cells exerts the superior T-cell functionality by delaying the exhaustion of CAR-T cells. Methods: This phase 1 dose escalation part (NCT04836507) was evaluated the safety and preliminary efficacy in patients with r/r LBCL. Anbal-cel was manufactured at GMP facility with fresh leukapheresis product. Patient was administered as a single intravenous dose at dose level 1 (2x105 cells/kg), DL2 (7x105 cells/kg) or DL3 (2x106 cells/kg). Lymphodepletion with cyclophosphamide (500mg/m2) and fludarabine (30mg/m2) was performed for 3 days prior to Anbal-cel infusion. Results: As of Jan 17 2022, 9 patients with r/r DLBCL were infused with Anbal-cel; 4pts at DL1, 3pts at DL2 and 2pts at DL2. Median age was 54 (range 26-71); all patients received 2 or more prior lines of therapy and 44% (4/9) received ≥4 prior line of treatment before the study. 78% (7/9) patients were refractory to their last treatment. 67% (6/9) of patients were at IPI 3-4 and 44% (4/9) of patients had bulky disease. No patient experienced DLT during the study. Of the 9 patients, 5 (56%) experienced CRS; 4 (44%) were grade 1 or 2 and one patient experienced grade 3 CRS. Median time to onset of CRS was 7 days (range, 1-16) with median duration of 4 days (range, 0-18). One patient dosed at DL3 experienced grade 2 ICANS, time to onset of ICANS was 7 days and lasted for 13 days. This patient had prior CNS involvement history before the study. Most commonly reported grade 3/4 AEs were neutrophil count decrease (6/9, 67%), anemia (5/9, 56%), thrombocytopenia (2/9, 22%), platelet count decrease (2/9, 22%) and no infection was reported. Complete response rate (CRR) was 78% and complete responses were observed at the lowest dose level and from patients expressing less than 10% CD19 at IHC; 3 complete responses (CR) at DL1, 2 CRs at DL2 & DL3 respectively. Dose-dependent CRC01 expansion was observed; median Tmax was 15.4, 15.8, 11.0 days at DL1, DL2 & DL3 each; median Cmax was 18,003, 30,103, 53,688 copies/ug gDNA at DL1, DL2 & DL3 each; median AUC0-28day was 679,125, 1,110,108, 2,852,235 copies/ug gDNA at DL1, DL2 & DL3 respectively. Conclusions: Anbal-cel demonstrated promising efficacy and tolerable safety profile in this dose escalation study. Based on this phase 1 study, phase 2 patient enrollment will be commenced in Mar 2022 to evaluate the response rate, duration of response of CRC01 as well as safety. In addition, various biomarker studies are planned to investigate the differential mode of action of Anbal-cel during phase 2 study. Clinical trial information: NCT04836507.
Demographics and treatment outcomes in patients with EBV+ PTLD treated with off-the-shelf EBV-specific CTL under an ongoing expanded access program in Europe: First analyses.
Authors: Choquet Sylvain , Chaganti Sridhar , Uttenthal Ben , Comoli Patrizia , Trappe Ralf Ulrich , Friedetzky Anke , Xing Baodong , Li Xiaoming , Polak Tobias Boy , Gamelin Laurence , Terwey Jan-Henrik , Dierickx Daan
Published: June 2022

7530

Background: Patients undergoing allogeneic hematopoietic cell transplant (HCT) or solid organ transplant (SOT) are at risk of developing Epstein–Barr virus driven post-transplant lymphoproliferative disorder (EBV+ PTLD), a rare hematologic malignancy, which is often aggressive and life-threatening. Patients with relapsed or refractory (r/r) EBV+ PTLD have few treatment options with poor outcomes, demonstrating a clear unmet medical need. Tabelecleucel is an investigational, off-the-shelf, allogeneic EBV-specific T-cell immunotherapy being studied in patients with serious EBV+ diseases (NCT04554914 & NCT03394365) that has demonstrated clinical benefit and favorable safety profile in the treatment of EBV+ PTLD after failure of rituximab (R) ± chemotherapy (Prockop, EBMT 2021, ATC 2021, ASH 2021). Methods: Atara Biotherapeutics supports an ongoing expanded access program (EAP) in Europe for patients with EBV+ diseases who have no other treatment options. Here we report demographics, efficacy and safety results of r/r EBV+ PTLD patients following SOT or HCT who presented between Jul 2020 and Nov 2021 and consented to research. Results: A total of 48 EAP requests from 9 countries for patients with EBV+ diseases were received. Twenty-two patients from 7 countries consented to this research: 16 EBV+ PTLD and 6 EBV+ non-PTLD. Of the 16 PTLD patients 15 received at least one dose of tabelecleucel. Overall, 9 out of 15 (60%) patients achieved a response as assessed by the treating physician, with 6 complete responses and 3 partial responses. Eight out of nine responses were seen after the first cycle. No adverse events were reported as related to tabelecleucel by the treating physician. Conclusions: The successful execution of this European EAP demonstrates the feasibility to deliver an off-the-shelf allogeneic EBV+ T-cell therapy in time-sensitive clinical situations when no other treatment options exist. These data show clinically meaningful outcomes for patients with r/r EBV+PTLD post-SOT or post-HCT treated with tabelecleucel consistent with previously reported favorable safety and efficacy profile (Prockop, ASH 2021).[Table: see text]
Acalabrutinib versus rituximab plus idelalisib or bendamustine in relapsed/refractory chronic lymphocytic leukemia: ASCEND results at 4 years of follow-up.
Authors: Jurczak Wojciech , Pluta Andrzej , Wach Malgorzata , Lysak Daniel , Simkovic Martin , Kriachok Iryna , Illés Árpád , De La Serna Javier , Dolan Sean , Campbell Philip , Musuraca Gerardo , Jacob Abraham , Avery Eric Joseph , Lee Jae Hoon , Usenko Ganna , Wang Min Hui , Yu Ting , Ghia Paolo
Published: June 2022

7538

Background: Acalabrutinib (acala) is a next-generation, highly selective, covalent Bruton tyrosine kinase (BTK) inhibitor approved for patients (pts) with chronic lymphocytic leukemia (CLL). In the primary analysis of ASCEND (median follow-up 16.1 mo), acala showed superior efficacy with an acceptable tolerability profile vs idelalisib (Id) plus rituximab (R) (IdR) or bendamustine (B) plus R (BR) in pts with relapsed/refractory (R/R) CLL (Ghia et al. J Clin Oncol. 2020;38:2849-2861). We report the results of the ASCEND study at ~4 years of follow-up. Methods: In this multicenter, randomized, open-label, phase 3 study (NCT02970318), pts with R/R CLL received oral (PO) acala 100 mg BID until progression or unacceptable toxicity or investigator’s (INV) choice of IdR (Id: 150 mg PO BID until progression or unacceptable toxicity; R: 375 mg/m2 x1 then 500 mg/m2 IV [8 total infusions]) or BR (B: 70 mg/m2 IV; R: 375 mg/m2 x1 then 500 mg/m2 IV [6 cycles]). Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety were assessed. Results: A total of 310 pts (acala, n=155; IdR, n=119; BR, n=36) were randomized (median age 67 y; del(17p) 15%, unmutated IGHV 74%, Rai stage 3/4 42%). At median follow-up of 46.5 mo (acala) and 45.3 mo (IdR/BR), acala significantly prolonged INV-assessed PFS vs IdR/BR (median not reached [NR] vs 16.8 mo; P<0.0001); 42-mo PFS rates were 62% for acala vs 19% for IdR/BR. In pts with del(17p), median PFS was NR (acala) vs 13.8 mo (IdR/BR; P<0.0001). In pts with unmutated IGHV, median PFS was NR (acala) vs 16.2 mo (IdR/BR; P<0.0001). Median OS was NR in both arms; 42-mo OS rates were 78% (acala) vs 65% (IdR/BR). ORR was 83% (acala) vs 84% (IdR/BR) (ORR + partial response with lymphocytosis: 92% [acala] vs 88% [IdR/BR]). AEs led to drug discontinuation in 23% of acala, 67% of IdR, and 17% of BR pts. Events of clinical interest (acala vs IdR/BR) included all-grade atrial fibrillation/flutter (8% vs 3%), all-grade hypertension (8% vs 5%), all-grade major hemorrhage (3% vs 3%), and grade ≥3 infections (29% vs 29%). Conclusions: At ~4 years of follow-up, acala maintained efficacy compared with standard-of-care regimens and a consistent tolerability profile in R/R CLL. Clinical trial information: NCT02970318. [Table: see text]
Analysis of peripheral neuropathy (PN) using clinician- and patient-reported outcomes (ClinRO and PRO) in the POLARIX study.
Authors: Trneny Marek , Fogliatto Laura , Gardner Faithlore Patrice , Flinn Ian W. , Larouche Jean-Francois , Haioun Corinne , Canales Albendea Miguel Angel , Goto Hideki , Hajek Roman , Salles Gilles A. , Qiu Jiaheng , Campinha-Bacote Avrita , Yan Mark , Kothari Rucha , Man Gabriel , Sahin Deniz , Hirata Jamie , Lee Calvin , Tilly Herve , Flowers Christopher
Published: June 2022

7561

Background: PN is an identified risk of anti-microtubule agents, including polatuzumab vedotin and vincristine. POLARIX (NCT03274492), a Phase III randomized, double-blind, placebo-controlled study comparing Pola-R-CHP with R-CHOP, demonstrated improved progression-free survival (PFS) with Pola-R-CHP (Tilly et al. NEJM 2022). Here, we evaluate the impact of Pola-R-CHP vs R-CHOP on PN using ClinRO and PRO data. Methods: Patients with previously untreated diffuse large B-cell lymphoma (DLBCL) received Pola-R-CHP or R-CHOP. ClinRO data were based on PN grading according to the NCI CTCAE v4.0. PRO data were generated from assessment of patient-reported PN symptoms at baseline and Day 1 of each cycle using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity (FACT-GOG/NTX) subscale, ranging from 0–44, with higher scores representing lower levels of PN (minimal clinically important difference: 1.38–3.68 [Cheng et al. Health Qual Life Outcomes 2020]). Results: At baseline, ClinRO and PRO symptom scores showed low PN burden (Table). Overall incidence of PN was comparable between treatment arms (Pola-R-CHP: 52.9%; R-CHOP: 53.9%); most events were grade 1, and incidence of grade 2 (Pola-R-CHP: 12.2%; R-CHOP: 15.5%) and grade 3 (Pola-R-CHP: 1.6%; R-CHOP: 1.1%) events were comparable between treatment arms. FACT-GOG/NTX survey completion was high in both arms (96% at baseline; >80% at other timepoints). When evaluated by cycle, ClinRO and PRO demonstrated that more patients experienced earlier onset PN with R-CHOP than with Pola-R-CHP (Table), with ̃10% more R-CHOP- than Pola-R-CHP-treated patients having clinician-reported PN in Cycle (C) 2–5, and a ̃+1-point difference (i.e. fewer symptoms) in PRO symptom scores in C3–6 with Pola-R-CHP vs R-CHOP; by C8+, and during follow up, rates and symptoms of PN were similar. PN symptoms resulted in fewer dose reductions (3.9% vs 8.2%) and drug discontinuations (0.7% vs 2.1%) with Pola-R-CHP vs R-CHOP. Duration of PN was similar for both treatments. Conclusions: In the POLARIX study, Pola-R-CHP did not result in different rates or severity of PN vs R-CHOP. According to ClinRO and PRO data, PN occurred later following initial exposure to Pola-R-CHP than to R-CHOP, and there were fewer dose modifications with Pola-R-CHP than with R-CHOP. Overall, the risk of PN was manageable. Clinical trial information: NCT03274492. [Table: see text]
Safety and clinical activity of belantamab mafodotin with lenalidomide plus dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM): DREAMM-6 arm-A interim analysis.
Authors: Quach Hang , Gironella Mercedes , Lee Cindy , Popat Rakesh , Cannell Paul , Kasinathan Ravi , Chopra Bikramjit , Rogers Rachel , Ferron-Brady Geraldine , Shafi-Harji Seema , Patel Nashita , Opalinska Joanna , Gupta Ira V. , Augustson Bradley
Published: June 2022

8017

Background: Belantamab mafodotin (belamaf; BLENREP) is a B-cell maturation antigen-targeting antibody–drug conjugate approved for patients (pts) with RRMM as monotherapy at 2.5 mg/kg Q3W. Preclinical data demonstrate synergy between belamaf and lenalidomide (Len), suggesting added benefit when combined with standard of care such as Len + dexamethasone (Dex). DREAMM-6 (NCT03544281) Arm A is evaluating belamaf in combination with LenDex in pts with RRMM. Methods: This ongoing, two-part, two-arm, open-label study included pts with RMMM previously treated with ≥1 line of therapy (LOT). Pts received 4 belamaf doses/schedules (1.9 mg/kg Q8W or Q4W; 2.5 mg/kg Q4W or Q4W SPLIT dose [50% on Days (D)1, 8] IV) in combination with Len (20 mg PO D1–21) and Dex (20 mg PO/IV D1, 8, 15, 22). Primary objectives were safety (including treatment-related [TR]AEs related to the combination belamaf and LenDex), tolerability, and efficacy (including overall response rate [ORR] defined as ≥partial response). Results: As of this interim analysis (data cut: July 23, 2021), 45 pts received ≥1 dose (12 at 1.9 mg/kg Q8W; 4 at 1.9 mg/kg Q4W; 16 at 2.5 mg/kg Q4W; 13 at 2.5 mg/kg Q4W SPLIT). Across cohorts, the median age was 68 y (range: 36–80). Thirteen pts (29%) had high-risk cytogenetics and 6 (13%) had extramedullary disease. Median prior LOT was 3 (range: 1–11) and 26 (58%) had prior Len treatment. The median duration of follow-up and ORR ranged across cohorts (Table). The median duration of response was only reached in the 1.9 mg/kg Q4W cohort (11.1 mo [95% CI: 3.7–not reached [NR]). At the time of data cut, median progression-free survival was not reached in the 1.9 mg/kg Q8W or 2.5 mg/kg Q4W cohorts. Gr ≥3 TRAEs occurred in 42–85%. Gr ≥3 keratopathy occurred in 0 pts in 1.9 mg/kg Q8W, 1 pt (25%) in 1.9 mg/kg Q4W, 8 pts (50%) in 2.5 mg/kg Q4W, and 6 pts (46%) in 2.5 mg/kg Q4W SPLIT cohorts. Conclusions: Belamaf + LenDex had a tolerable safety profile, with no new safety signals identified in pts with RRMM. AEs, including keratopathy, were common but manageable with dose modifications. Encouraging clinical activity is observed with this combination in pts with RRMM. Follow-up/correlative studies are ongoing. Funding: GSK (Study 207497); drug linker technology licensed from Seagen Inc.; mAb produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT03544281. [Table: see text]
Synergistic effects of low-dose belantamab mafodotin in combination with a gamma-secretase inhibitor (nirogacestat) in patients with relapsed/refractory multiple myeloma (RRMM): DREAMM-5 study.
Authors: Lonial Sagar , Grosicki Sebastian , Hus Marek , Song Kevin W. , Facon Thierry , Callander Natalie Scott , Ribrag Vincent , Uttervall Katarina , Quach Hang , Vorobyev Vladimir I. , Min Chang Ki , Cheng Shinta , Smith L. Mary , Yu Jing , Collingwood Therese , Holkova Beata , Kremer Brandon , Gupta Ira , Richardson Paul G. , Minnema Monique C.
Published: June 2022

8019

Background: Preclinical data demonstrate that nirogacestat, a gamma-secretase inhibitor, may increase cell-surface levels of a B-cell maturation antigen (BCMA) and reduce soluble BCMA levels, which could enhance anti-BCMA agent activity in multiple myeloma. In the DREAMM-5 (NCT04126200) Phase I/II platform trial belantamab mafodotin (belamaf; BLENREP), a BCMA-targeting antibody-drug conjugate, is being evaluated in combination with nirogacestat to determine if the combination can result in similar efficacy and an improved ocular safety profile compared to the currently approved belamaf schedule (single agent dose 2.5 mg/kg Q3W) in patients with RRMM which showed a 31% overall response rate (ORR) and 44.5% Gr3/4 keratopathy (BLENREP US prescribing information). Methods: This cohort within the DREAMM-5 nirogacestat combination sub-study has a sequential dose-exploration (DE) phase evaluating 0.95 mg/kg Q3W belamaf with 100 mg BID nirogacestat continuously, followed by a randomized cohort expansion (CE) comparing the combination to a belamaf 2.5 mg/kg Q3W arm. Results: Preliminary results from the 10 patients (pts) in the DE cohort with low-dose belamaf + nirogacestat are presented in this abstract. Pts had a median (range) of 4.5 (3–10) prior lines of therapy. At time of data cut-off (Nov 15, 2021), pts received a median (range) of 7 cycles (1–26). The ORR was 60% (n=6/10) and 20% (n=2) achieved a very good partial response (Table). The key emergent adverse events (AEs) included ocular events (n=7 [70%]; ≥Grade [Gr] 3, n=2 [20%] of which Gr 3 keratopathy was reported in 1 pt [10%]), diarrhea (n=7 [70%]; Gr 3, n=1 [10%]) and hypophosphatemia (n=7 [70%]; Gr 3, n=1, [10%]). There were 2 Grade 5 AEs, neither of which were related to study treatment. No pt permanently discontinued study due to treatment related AEs. Conclusions: Encouraging clinical activity and a manageable safety profile is observed with low dose belamaf (0.95 mg/kg Q3W) + nirogacestat (100 mg BID continuously) in pts with RRMM. This ongoing sub-study is actively recruiting patients and will continue to evaluate belamaf + nirogacestat efficacy and safety. Updated results will be reported at the congress. Funding: GSK (208887); drug linker technology licensed from Seagen Inc.; mAb produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04126200. [Table: see text]
Health-related quality of life (HRQoL) in patients with relapsed/refractory multiple myeloma (RRMM) receiving real-life current standard of care (SOC) in the LocoMMotion study.
Authors: Delforge Michel , Moreau Philippe , Einsele Hermann , De Stefano Valerio , Lindsey-Hill Joanne , Vincent Laure , Mangiacavalli Silvia , Perrot Aurore , Ocio Enrique , ten Seldam Silene , in ’t Groen-Damen Ester , Semerjian Maria , Strulev Vadim , Schecter Jordan Mark , Roccia Tito , Gries Katharine S. , Nesheiwat Tonia , Wapenaar Robert , Mateos Maria-Victoria , Weisel Katja
Published: June 2022

8030

Background: Evaluation of patient (pt)-reported outcomes provides insight into how real-life SOC treatments (tx) affect HRQoL for pts with RRMM. LocoMMotion (NCT04035226) is the first prospective, multinational study of real-life SOC in triple-class exposed pts with RRMM. Here, we present measures of symptoms, functioning, and overall HRQoL. Methods: LocoMMotion is a prospective, noninterventional study across 76 sites (63 European; 13 US). Pts had received ≥3 prior lines of therapy (LOT) or were refractory to PI and IMiD; received PI, IMiD, and anti-CD38 mAb; and had disease progression during/after last LOT. Real-life SOC tx were defined as those used in local clinical practice. The questionnaires were EORTC QLQ-C30, 4 single items from EORTC QLQ-MY20, and EQ 5D-5L. HRQoL was assessed at baseline (BL), day 1 of each tx cycle, end of tx visit, and during the follow-up period (every 4 weeks). Improvement compared to BL health status was evaluated using established thresholds. Within-group change was assessed using mixed models for repeated measures. Results: Questionnaire completion for pts in the LocoMMotion study (N=248; 54.4% male; median age 68 yrs; median 4.0 [range, 1–20] cycles of SOC) was 75.6% during SOC tx. Most pts did not achieve meaningful improvement in PRO scores, defined by a literature-based minimally important difference of 10 points in mean score. This was most pronounced in pain symptoms (62% of pts had no meaningful improvement during the first 3 months of tx; 55% had no improvement during full tx duration). For the overall population, the least square (LS) mean changes from BL during SOC tx and subsequent LOT are described (Table). Pts who achieved very good partial response and better during SOC tx had greater improvement in PRO scores, including in LS mean change for pain score (-14.9 [95% confidence interval (CI): -22.9, -7.0]). Conclusions: In this first prospective study of real-life current SOC in triple-class exposed pts, limited gains in HRQoL were reported, most notably in pain symptoms. There is an urgent need for effective therapies that can help pts achieve deep responses and delay disease progression, as these are associated with improved HRQoL. Clinical trial information: NCT04035226. [Table: see text]