bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved pathologic complete response rates for triple-negative breast cancer in the I-SPY2 Trial.
Authors: Yee Douglas , Shatsky Rebecca Arielle , Yau Christina , Wolf Denise M. , Nanda Rita , van 't Veer Laura , Berry Donald A. , DeMichele Angela , Esserman Laura ,   I-SPY2 Consortium
Published: June 2022

591

Background: The I-SPY2 Trial evaluates multiple investigative agents in neoadjuvant breast cancer therapy with the primary endpoint of estimated pathologic complete response (pCR) rate. As a platform phase 2 trial it utilizes an adaptive design to compare new regimens with control chemotherapy (weekly paclitaxel followed by AC). Methods: Specific regimens are assigned based on clinically relevant signatures, including triple negative breast cancer (TNBC). Drug regimens graduate from the trial when the predicted pCR rate in any signature meets the pre-specified threshold of 85% probability of success in a hypothetical 300-patient, 1:1 randomized, phase 3 trial. The strong correlation between pCR rate and event free survival has been reported. To establish the benefit of administering investigational agents in combination with control weekly paclitaxel x 12 in TNBC, we report estimated pCR rates for the first 7 investigational agents. Results: TNBC accounted for 37% (363/987) of enrolled patients. Only veliparib and carboplatin (VC) and pembrolizumab (Pembro) met the graduation criteria for TNBC. However, compared to control chemotherapy, each drug tested in TNBC resulted in a numerically superior pCR rate compared to control. These findings imply that stratification of TNBC by response-predictive biomarkers may lead to improved pCR rates. For example, we have used gene expression profiling to further refine TNBC classification into Immune enhanced (Immune+), Immune-/DNA Repair Deficient (DRD)+, and Immune-/DRD- classes. TNBC identified as immune enhanced (63%) have an 89% pCR rate to pembrolizumab, while VC is less effective with pCR rate of 71%. Similarly, Immune-/DRD+ (11%) identifies TNBCs with a 80% pCR rate to VC, while pembrolizumab’s pCR rate in this group is only 33%. For tumors that are neither immune enhanced or DRD-positive (Immune-/DRD-; 25%) show numerically improved pCR rates for neratinib (20%), MK2206 (25%), ganitumab (24%), and ganetespib (22%) compared to control (12%). pCR rates for VC (10%) and pembrolizumab (20%) in this group were similar to drugs that did not graduate. For TNBC, many agents in I-SPY2 showed numerically improved pCR rates compared to conventional chemotherapy even when they did not meet our specified definition of graduation. Conclusions: Further refinement of TNBC signatures should yield improved therapeutic strategies while also sparing women unnecessary systemic therapy. Clinical trial information: NCT01042379. [Table: see text]
Real-world effectiveness of prophylactic granulocyte colony-stimulating factor (G-CSF) early (week 1) and late (weeks 2-3) in the cycle for the prevention of febrile neutropenia (FN) among patients (pts) with breast cancer (BC) after high FN–risk chemotherapy (chemo).
Authors: Blayney Douglas W. , Cummings Joyner Alice Kate , Jarvis John , Nunag Dominic , Wells Jasmine , Huang Lan , Mohanlal Ramon W.
Published: June 2022

599

Background: G-CSF mitigates chemotherapy-induced neutropenia (CIN) and reduces FN risk. G-CSF moves the nadir of absolute neutrophil count (ANC) earlier (to week 1) in the chemo cycle and shortens nadir duration (Crawford, NEJM 1991), suggesting the potential for suboptimal CIN protection early (week 1) in the chemo cycle. The relative FN risk in week 1 vs. weeks 2-3 of the cycle with G-CSF is unknown and was analyzed compared with no G-CSF in the real-world setting with high FN risk chemo. Methods: Using a database of administrative claims representing 100% of fee-for-service Medicare, we analyzed BC pts who initiated docetaxel (T), doxorubicin (A), or cyclophosphamide (C) monotherapy or combination therapy between 01/01/2015 – 12/31/2019. Sample pts included adults aged ≥ 65 years with continuous coverage in Medicare Parts A, B, and D for 6 months before and 20 days after chemo initiation. Pts were categorized as receiving vs. not receiving G-CSF therapy within 3 days after chemo. Rate of FN events starting in week 1 vs. weeks 2-3 in cycle 1 was calculated. We defined FN as an inpatient admission with a primary or secondary diagnosis of neutropenia and measured the interval between chemo initiation and FN admission. Results: Among 18,788 Medicare beneficiaries with BC treated with T, A, and/or C, 72% received G-CSF therapy. More pts receiving G-CSF were treated with ≥ 2 of T, A, and/or C compared to pts who did not receive G-CSF (71% vs. 51%). Overall FN incidence in cycle 1 was significantly lower among pts receiving G-CSF (4.0%; n=546) compared to pts not receiving G-CSF (8.8%; n=462) (p<0.0001). In pts with G-CSF, 81% (440/546) of all 1st-cycle FN events started in week 1 vs. 19% (106/546) in weeks 2-3. In pts not receiving G-CSF, the start of 1st-cycle FN events was more equally distributed: 41% (190/462) started in week 1 vs. 59% (272/462) in weeks 2-3. Results were robust to sensitivity analyses restricted to pts receiving ≥ 2 of T, A, and/or C. The rates of 1st-cycle FN events starting in weeks 1 and 2-3 with and without G-CSF following chemo initiation is shown below. Conclusions: Prophylactic G-CSF was highly effective for the prevention of FN in weeks 2-3, but relatively ineffective in week 1 of cycle 1 in the real-world setting, leaving pts largely unprotected during the first week. This represents an unmet medical need in week 1 of the cycle, despite use of G-CSF. Clinical trial information: NCT03294577. [Table: see text]
Impact of high-deductible health plans on delays in metastatic cancer diagnosis.
Authors: Trad Nicolas Karim , Hassett Michael J. , Zhang Fang , Wharam J. Frank
Published: June 2022

6503

Background: High-deductible health plans (HDHPs) have grown rapidly in recent years, and now cover over one-half of U.S. workers. Patients in HDHPs are liable for the costs of all cancer-related care until their annual deductible is met, with the exception of screening tests such as colonoscopy and mammography. Due to increased out-of-pocket obligations, patients may postpone presenting for concerning symptoms or diagnostic testing, leading to delayed diagnosis. We therefore assessed the impacts of HDHPs on the timing of metastatic cancer detection. Methods: Using a nationally representative cohort of privately insured members in a national commercial and Medicare Advantage database (2003-2017), we studied 345,401 individuals age 18-64 years whose employers mandated a switch from a low-deductible (≤$500) plan to a high-deductible (≥$1,000) plan. Our control group consisted of 1,654,775 contemporaneous individuals whose employers offered only low-deductible plans. Both groups had a 1-year baseline period when all members were enrolled in low-deductible plans, and we followed members for a maximum of 13.5 years. Participants were matched with respect to age, gender, race/ethnicity, morbidity (ACG) score, poverty level, geographic region, employer size, baseline primary cancer, baseline medical and pharmacy costs, and follow-up duration. We used a validated claims-based algorithm to detect incident metastatic cancer diagnoses. We assessed time to metastatic cancer diagnosis in the baseline period (pre-HDHP switch) and follow-up period (post-HDHP switch) using a weighted Cox proportional hazards model. Results: After matching, there were no systematic differences between the HDHP and control groups with regard to observable baseline characteristics (standardized differences < 0.1). The mean age of participants was 42 years and the mean ACG score was 0.75. 49% were female, 48% lived in low-income neighborhoods, and 62% were White. We detected 1,668 metastatic events over a mean follow-up period of 38 months. There were no differences in time to metastatic diagnosis in the baseline year, prior to the HDHP switch (HR 0.96, p = 0.67). After employer-mandated HDHP switch, HDHP participants had lower odds of metastatic cancer diagnosis (HR 0.88, p = 0.01), indicative of delayed detection relative to the control group. Conclusions: Compared with conventional health plans, HDHPs are associated with delayed detection of metastatic cancer. These findings imply that patients postpone seeking care for concerning symptoms or defer diagnostic testing when exposed to high cost-sharing. Given recent advances that have improved survival of patients with advanced-stage cancers, future research efforts should investigate the impacts of HDHPs on quality of life, engagement in palliative care, and use of treatments in this patient population.
Growing financial burden from targeted oral anticancer medicines among Medicare beneficiaries with cancer.
Authors: Li Meng , Liao Kai-Ping Eric , Pan I-Wen , Shih Ya-Chen Tina
Published: June 2022

6504

Background: The rapidly rising costs of targeted oral anticancer medicines (TOAMs) raise concerns over their affordability. Our goal was to examine recent trends in the uptake of TOAMs among cancer patients with Medicare Part D, the share of TOAM users who reached catastrophic coverage, and the annual spending on TOAMs in the catastrophic phase. Methods: Using the 5% SEER-Medicare, we included patients aged 65 and older who had one primary cancer diagnosis between 2011 and 2016. We included person-years where patients were enrolled in a Part D plan for the entire year, did not receive the Low-Income Subsidy (LIS) at any time of the year, and received anticancer systemic therapies. We estimated the trends in the share of patients who used TOAMs, the percentage of TOAM users reaching catastrophic coverage, and the total and patient out-of-pocket spending on TOAMs in the catastrophic phase in a year. Results: From 2011 to 2016, the uptake of TOAMs among our study population increased from 3.6% to 8.9%. The percentage of non-LIS TOAM users who reached catastrophic coverage increased from 54.6% to 60.3%. Among those who reached the catastrophic phase, mean total gross spending on TOAMs in the catastrophic phase increased from $16,074 to $64,233 and mean patient out-of-pocket spending from $596 to $2,549. The mean 30-day total spending increased from $4,011 to $8,857, and the mean 30-day out-of-pocket spending from $154 to $328. Conclusions: The high and growing burden from TOAMs highlighted the need for reining in drug prices and capping out-of-pocket spending.
Validity and efficiency of progression-free survival (PFS)-2 as a surrogate endpoint for overall survival (OS) in advanced cancer.
Authors: Woodford Rachel , Zhou Deborah , Kok Peey-Sei , Lord Sally , Friedlander Michael , Marschner Ian , Simes John , Lee Chee Khoon
Published: June 2022

6518

Background: PFS is used widely as a primary endpoint in oncology trials and as a surrogate for OS. PFS-2, defined as time from randomization to progression on second line therapy, is potentially a more reliable surrogate than PFS but requires additional follow-up time. We evaluated the validity and efficiency of PFS-2 as a surrogate endpoint for OS and compared its performance with PFS. Methods: We performed an electronic search to identify randomized trials of advanced solid tumors reporting on PFS, PFS-2 and OS as pre-specified endpoints. We compared the correlations in the relative treatment effect for OS with PFS and PFS-2. We extracted data from Kaplan-Meier survival curves to create individual patient data to estimate time to statistical significance (TSS), defined as logrank P < 0.05. We further computed the samples size (person-year follow-up) required to reach statistical significance and assessed for the effect of survival post-progression (SPP). If trials failed to reach statistical significance for a particular endpoint, the maximal follow-up time was used. Results: Our study consisted of 39 analysis units with 20714 patients. Correlations of the OS treatment effect with the PFS and PFS-2 treatment effects were r= 0.12 (95% CI 0.00-0.13) and r= 0.67 (95% CI 0.08-0.69) respectively. The median differences in TSS between OS with PFS, OS with PFS-2, and PFS2 with PFS were 8.7, 8.4, and 3.2 months respectively. For trials with a SPP < 12 months, smaller differences in the median TSS as compared to SPP ≥12 months were seen. The median differences in follow-up required to reach statistical significance were 329, 151 and 122 person-years (PY) respectively. These differences were equivalent to a median 18.3% increase in sample size required for PFS-2 over PFS. The median increase in sample sizes were 18.2% and 22.3% for trials with SPP < 12 and ≥12 months respectively. Conclusions: PFS-2 has a stronger correlation with OS benefit than PFS. When PFS-2 is used as primary endpoint, trials will require an additional median 3.2 months to achieve statistical significance, and an additional 18.3% increase of sample size over PFS. PFS-2 balances between improved correlation with OS but modest increase in follow-up time and sample size. PFS-2 should therefore be considered as a primary endpoint in future trials of advanced cancers.[Table: see text]
Feasibility of systematic screening for unmet social determinants of health (SDoH) needs and associated resource utilization in ambulatory oncology.
Authors: Odai-Afotey Ashley , Haakenstad Ellana , Neville Bridget A. , Lipsitz Stuart R. , Zhang Sunyi , McCleary Nadine Jackson
Published: June 2022

6535

Background: Addressing unmet SDoH needs may reduce interruptions to cancer care caused by ED visits and hospitalizations (EDH). We aimed to determine feasibility of systematic screening for unmet patient-reported SDoH needs within a large tertiary academic comprehensive cancer center and association of unmet needs with EDH. Methods: We conducted a cross-sectional analysis of SDoH needs among new oncology patient (pts) consults from 5/15-9/21 at Dana-Farber Cancer Institute (DCFI). Pts completed an intake questionnaire including demographics, disease, and SDoH needs of financial distress, health literacy/numeracy, social isolation on a dichotomous or 5-point Likert scale. We ran bivariate and multivariable models on the association between demographics, SDoH and EDH within 30 days of consult using robust generalized estimating equations controlling for clustering by consult provider. Results: 125,997 unique new consults were seen from 5/15 – 9/21 of which 20,913 completed the intake questionnaire and were alive at 30 days after consult. Respondents were age 40-64 (50%), female (60%), non-Hispanic (84%), White (90%) and English speaking (97%), and 7% had an EDH within 30 days of consult. The most reported SDoH need was limited health numeracy (26%). In bivariate analysis, factors associated with ED visits were: non-English language, lung or GU/GYN cancer, living > 25 mi from DFCI and limited health literacy and numeracy (all p < 0.05). Demographics associated with hospitalizations included: White race and English as a primary language (EPL) (both p < 0.05). Multivariable analysis showed female gender (OR 1.53, p < 0.01), lung (OR 3.22*) and GU/GYN (OR 2.21*) (p < 0.05 for both) cancer, and living > 25 mi from DFCI (OR 2.50, p < 0.0001) were associated with increased likelihood of ED visit while EPL (OR 1.80, p < 0.05) and GU/GYN (OR 1.65, p < 0.01*) cancer were associated with increased likelihood of hospitalization. Conclusions: It is feasible to systematically screen for unmet SDoH which are associated with increased frequency of ED visits. Differences in characteristics associated with ED vs. hospitalization could indicate possible bias or suggest SDoH needs as a reason for avoidance of costly medical care. Further study will expand SDoH screening and measure impact of resource matching to reduce disruptions to cancer care. [Table: see text]
Theory-guided assessment of barriers and facilitators to adequate informed consent for childhood cancer clinical trials: Using the Exploration, Preparation, Implementation, Sustainment (EPIS) framework.
Authors: Aristizabal Paula , Vu Britney , Perdomo Bianca , Kaiser Bonnie N , Nodora Jesse , Thornburg Courtney D , Martinez Elena , Aarons Gregory A
Published: June 2022

6539

Background: To participate in childhood cancer clinical trials, parents/legal guardians must provide informed consent (IC), which is a fundamental ethical right. However, barriers to achieving valid IC include: use of medical jargon, misunderstanding about clinical trials procedures, tremendous emotional distress surrounding the initial cancer diagnosis, and the complexity and length of the IC forms. There are scarce data on using theory to assess perspectives of parents of children with cancer on barriers and facilitators for adequate IC in diverse populations. Methods: Using implementation science theory and methods, we assessed parent-reported barriers and facilitators to adequate IC, in a convenience sample that included a significant number of Hispanics. Twelve qualitative semi-structured interviews and 224 open-ended surveys were conducted with 236 parents of children with newly-diagnosed cancer at Rady Children’s Hospital-San Diego, a large quaternary children’s hospital in California. Fifty-three percent of participants were Hispanic and 38% were monolingual Spanish-speakers. We utilized the Exploration, Preparation, Implementation, Sustainment (EPIS) Framework, specifically domains of outer context, inner context, bridging and innovation factors. Four main codes (IC concepts and delivery; desired clinical trial information; motivations and emotions related to clinical trial enrollment; and potential areas for interventions) were used as a coding guide for analysis. Interviews and surveys were transcribed and coded for thematic analysis by three independent coders to identify key barriers and facilitators. Results: Four main themes were identified as barriers: 1) Complexity of the IC forms and discussion (lengthy, confusing, not available in Spanish, and use of medical jargon); 2) parents feeling emotionally overwhelmed, anxious and pressured around the IC; 3) parents viewing the clinical trial as the only treatment option; and 4) mistrust and fear of clinical trial procedures. Four IC facilitators were identified: 1) simpler explanations of study procedures; 2) provider flexibility for accommodations when delivering the IC, including psychosocial support; 3) active promotion of voluntariness and trust; and 4) supplemental education in lay language, including request for peer-education, decision aids, and navigation to “bridge the provider-patient gap.” Conclusions: Our implementation science approach identified multiple barriers and facilitators to adequate IC in a diverse sample of parents. Findings can inform potential interventions to enhance IC for childhood cancer clinical trials, including the use of decision aids, peer-navigation, and interventions tailored to the language and culture of the individual.
Rural disparities in oncology patient portal enrollment and use.
Authors: Morris Bonny , Topaloglu Umit , Lesser Glenn Jay , Strowd Roy E. , Weaver Kathryn E. , Falk Derek Sean , Bell Ronny A.
Published: June 2022

6557

Background: Patient portals support patient access, engagement, and care coordination, yet could also widen the digital divide and exacerbate disparities among vulnerable populations. There is emerging evidence that racial/ethnic minority patients are less likely to use portals, yet prior research has not examined potential rural differences. We identified sociodemographic factors associated with portal enrollment and use among a racially and geographically diverse population of cancer patients. Methods: We retrospectively examined portal enrollment and use at an NCI-designated comprehensive cancer center from January 2015 until February 2022 among patients 18+ years old with a neoplastic disease diagnosis (ICD-10-CM C00-D49). Potential predictors included gender, race/ethnicity, marital status, age, rural (Rural-Urban Continuum Codes [RUCC] 4-9) vs nonrural (RUCC 1-3) residence, residential distance from the cancer center, and time since diagnosis. We used multivariable logistic regression to generate odds ratios (ORs) for portal enrollment and having ever sent a portal message, and Poisson regression to determine incidence rate ratios (IRRs) for number of logins and number of healthcare team interactions (portal messages or appointment requests), controlling for ICD-10 diagnosis (SAS 9.4). Results: We identified 11,333 patients (average age 67 years, 59% female, 24% rural, 10% Non-Hispanic Black, 1% Hispanic, 20% non-melanoma skin cancer, 14% breast cancer, 9% lung cancer). 36% of patients had enrolled in the portal, and of these, 80% had sent at least one message. Patients logged in a median of 203.5 times and had a median of 19 portal interactions. Rural residents were less likely to enroll in the portal than urban patients (28% vs 38%, p < 0.0001). Non-Hispanic Black patients and Hispanic/Latinx patients were less likely to enroll in the portal compared with non-Hispanic White patients (22% and 27%, respectively, vs 38.5%, p < 0.0001). Women, younger patients, more recently diagnosed cancer patients, and patients who were married/ partnered were significantly more likely to enroll. In multivariable analysis controlling for cancer type, rural patients were half as likely to enroll in the portal (OR: 0.48 [0.43-0.54]). Among those enrolled, rural residents were 25% less likely to have ever sent a portal message (OR: 0.75 [(0.62-0.92]), and had nearly half the login and interaction rates (IRR: 0.66 [0.66-0.67]; IRR: 0.58 [0.58-0.59], respectively). Patients who were Non-Hispanic Black, Hispanic, or unmarried were also significantly less likely to enroll or engage in the portal. Conclusions: Patient portals remain underutilized among cancer patients, despite an increased reliance on virtual communications in the COVID era. Interventions to support portal engagement among rural residents and racial/ethnic minority patients are needed to avoid potentially exacerbating health disparities.
An examination of translated content on NCI-designated cancer websites with a focus on breast and colorectal cancer.
Authors: Aslanova Minira , Buckley Megan C , Karim Gres
Published: June 2022

6576

Background: One unforeseen implication of the pandemic has been a greater reliance on health information sharing via the Internet. This is complicated by the fact that many healthcare websites and online resources fail to consider Limited English Proficiency (LEP) when designing websites that relay essential health information. We aimed to quantify the extent to which NCI-Designated Cancer Center websites provide language accessibility. Methods: Over the course of 2021, we performed a cross-sectional review of translation services and available languages on NCI-Designated Cancer Center websites. This study was particularly focused on both breast cancer and colorectal cancer portions of these websites. The primary out-comes were as follows: option of translated content, presence of more than one language, and method by which the translation was performed (written text vs. Google scholar). We referred to the 2015 US language map for the percentage of LEP by state. Results: Of the 71 NCI-Designated Cancer Centers, 56 (78.9%) were without translation, and 15 (21.1%) used either manual translation or displayed a link for Google translate. Of the 15 centers who offered translated content on their website, 15/15 (100%) had more than one language available in the drop down list. Spanish (100%) was the most common language available. In terms of Limited English Proficiency, 25 of 71 (35.21%) NCI-Designated Cancer Centers were located in states where greater than 10% of the population is defined as having LEP, and yet, only 5 of these centers (20.0%) had languages other than English featured. We observed no significant relationship between the state LEP percentile and the number of NCI-Designated Cancer Centers offering website translation services within that state. Additionally, no appreciable differences in language availability were observed between breast cancer and colorectal cancer. Conclusions: Overall, only a fraction of NCI-Designated Cancer Centers actually translate the content of their websites. In New York for example, despite having the highest percentage of residents with LEP at 19.345%, only one of ten NCI-Designated Cancer Centers within the state had a website with language translation. We believe this represents a missed opportunity as language inaccessibility may contribute to delays in care for non-English speaking patients, particularly in a post pandemic world, further exacerbating health care disparities among patient populations.
Longitudinal changes in financial burden in patients with colorectal cancer treated with curative intent: Primary results of EAQ162CD.
Authors: Kircher Sheetal Mehta , Duan Fenghai , Underwood Ellen , Gareen Ilana F. , Sicks Jorean , Sadigh Gelareh , Suga Jennifer Marie , Kehn Heather , Mehan Paul Tracy , Bajaj Rajesh , Hanson David Sam , Dalia Samir , Acoba Jared David , Taylor Michael A , Wagner Lynne I. , Carlos Ruth C
Published: June 2022

6597

Background: We prospectively assessed financial burden (FB) due to treatment costs among patients with colorectal cancer (CRC) recruited by NCI Community Oncology Research Program (NCORP) sites. Methods: Patients with newly diagnosed CRC treated with curative intent enrolled through NCORP sites and completed the FACIT Comprehensive Score for Financial Toxicity (COST) instrument at 0-, 3, 6, and 12 months. Higher COST score (range 0-44) indicates greater financial well-being. Effects of demographic, clinical, self-efficacy and safety net affiliation on FB were assessed using linear mixed modeling with compound symmetry covariance structure to account for measurement correlation from the same subject. Results: In 450 patients (mean age 61, 47% female, 84% white, 64% colon, 31% rectal) attrition was comparable across demographics, clinical variables and baseline FB. Higher COST score was linearly correlated with time. Increasing age, income less than $60,000 (vs. less than $29,999), higher self-efficacy, and higher neighborhood socioeconomic status (nSES) predicted a higher COST score; these effects were not moderated by time. Chemotherapy receipt, insurance type, and treatment at a safety net hospital did not predict COST score. Conclusions: Among those with CRC treated with curative intent in community settings, FB improves over the 12 months post diagnosis. Individual and neighborhood level social determinants of health are protective from financial fragility.[Table: see text]
Autologous CD19-directed CAR T cells produced by novel PrimeCARmanufacture platform exhibit safety, efficacy, and long persistence profiles in relapsed/refractory B-lineage acute leukemia (r/r B-ALL).
Authors: Li Shiqi , Yang Zhi , Chen Zucong , Li Yu , Liu Lin , Yuan Zhongtao , Zhang Yingzi , Luo Le , Fang Lihua , Chen Yingnian , Zhang Qianzhen , Shen Junjie , Li Yunyan , Wang Linling , Wang Meiling , Zhu Wei , Wang Sanbin , Qian Cheng
Published: June 2022

7008

Background: CD19 chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy in the r/r B-ALL. However, the life-threatening side effects especially high grades of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) limited its wide application. To overcome these limitations, we established a novel PrimeCAR platform based on moderate activation and short expansion to manufacture MC-1-50, an autologous CD19-directed CAR T cell. Our preclinical study showed that MC-1-50 exerted a great efficacy and less cytokines secretion. Methods: In this Phase I /II study (NCT04271410), CAR T cells were manufactured by PrimeCAR platform, which reduces manufacture periods to about 2 days. T cells were transducted with a lentiviral vector encoding a humanized CD19 specific scFv following 4-1BB and CD3ζ cytoplasmic domain. Patients (pts) received single-dose of MC-1-50 at dose level 1 (1×105 CAR+/kg), level 2 (3×105 CAR+/kg), and level 3 (1×107 CAR+ totally, ranged 1.67-3.85×105 CAR+/kg). Pts were pre-conditioned with fludarabine (25-30 mg/m2) and cyclophosphamide (200-300 mg/m2) daily for 3 days. Toxicity was graded by CTCAE, CRS and ICANS were graded by ASTCT criteria. Results: As of Feb 10, 2022, 13 pts with r/r B-ALL were infused with MC-1-50. Disease characteristics and outcomes are shown in the table. No DLTs were reported. Eleven pts (84%) experienced CRS, including 7 (54%) at grade 1 and 4 (30%) at grade 2, no ≥ 3 CRS were observed. One pts (7%) experienced grade 1 ICANS, no ≥ 2 ICANS occurred. The Tmax for IL-6 was detected around day 11 (123.3±165.16 pg/ml). There were similar low secretion features of other cytokines, which is consistent with low CRS and ICANS. In all dose levels, 13 pts finished 1M evaluation and the CR rate in 1M is 100%. Four pts finished 3M evaluation and the CR rate in 3M is 75%, 1 pts relapsed at the month 3 with CD19 mutation. One pts had a CR statue at the month 11. Cmax for CAR copy number in 3 dose levels are similar and the average number of Cmax of CAR is 275901.6 copies/ug genomic DNA. Conclusions: PrimeCAR platform could produce CAR T cells in very short time with high percentage of Tscm. Treatment of r/r B-ALL at very low dose resulted in excellent safety profile, while exhibited a promising efficacy. That make this PrimeCAR platform potential for outpatient administration in the future. Clinical trial information: NCT04271410. [Table: see text]
Epcoritamab (epco) with gemcitabine + oxaliplatin (GemOx) in patients (pts) with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant (ASCT) induces high response rate even in pts failing CAR T therapy.
Authors: Brody Joshua , Wahlin Bjorn E. , Phillips Tycel Jovelle , Costello Régis , Lugtenburg Pieternella , Cordoba Raul , Wang Liwei , Wu Jun , Elliott Brian , Abbas Aqeel , Jørgensen Judit
Published: June 2022

7527

Background: Pts with R/R DLBCL who fail or are ineligible for ASCT have very poor outcomes with standard palliative chemotherapy. Rituximab + GemOx had a complete response rate of 33% (Cazelles et al, Leuk Lymphoma 2021); novel approaches are needed. Epco is a subcutaneously administered bispecific antibody targeting CD3 on T cells and CD20 on B cells. In the EPCORE NHL-1 dose-escalation trial, epco had manageable safety and antitumor activity in heavily pretreated B-cell NHL including DLBCL. EPCORE NHL-2 is a phase 1/2 trial evaluating epco + standard B-cell NHL therapies; shown here are results from arm 5 (NCT04663347). Methods: Adults with R/R CD20+ DLBCL who failed or were ineligible for ASCT received epco (QW, cycle [C] 1–3; Q2W, C4–9; Q4W, C≥10) and GemOx (Q2W, C1–4) until disease progression or unacceptable toxicity (28 d/C). Step-up epco dosing and prophylactic corticosteroids were required in C1 to mitigate CRS. Response was assessed by PET-CT per Lugano 2014 criteria. Results: As of Dec 1, 2021, 27 pts (median age, 71 y; range, 47–87 y) had received epco + GemOx (epco 24 mg, n=3; 48 mg, n=24). Most were stage IV (56%), primary refractory (56%), and refractory to last therapy (70%). Median number of prior therapies was 2 (range, 1–13). Median follow-up was 6.0 mo (range, 1.0–11.1), with treatment (Tx) ongoing in 16 pts (59%). The most common Tx-emergent AEs were CRS (70%), thrombocytopenia (70%), neutropenia (56%), anemia (52%), and infections (52%). CRS events were all grade (G) 1/2, with most cases occurring in C1; all cases resolved. One pt had ICANS (G3); 1 pt had tumor lysis syndrome (G3). Six pts (22%) had G5 AEs; investigator could not rule out contribution of epco in 2 pts: small bowel perforation in pt (72 y) with transformed DLBCL and extensive gastrointestinal involvement (had complete metabolic response [CMR]); acute hepatitis/multiorgan failure in pt (68 y) with transformed DLBCL and liver involvement (had CMR). Of 4 pts with fatal AEs unrelated to epcoritamab by investigator, 2 (87 y) had primary refractory disease and 2 (74 y) had multiple comorbidities. Response is shown in the Table. At the time of data cut, 65% of responders remained in response with the longest duration of response 6.9 mo. All 3 pts with prior CAR T remained on Tx and in response (2 CMR and 1 partial metabolic response [PMR]). Conclusions: When considering individual safety profiles of epco or GemOx, no unexpected safety findings were observed for epco + GemOx. In this R/R population with high unmet need, these initial data are encouraging and warrant further clinical evaluation. Clinical trial information: NCT04663347. [Table: see text]
First-in-human phase I study of a ROR1-targeting bispecific T-cell engager (NVG-111) shows evidence of efficacy in patients with relapsed/refractory CLL and MCL.
Authors: Jasani Parag , Townsend William , Asher Samir , Tayabali Sarrah , Tucker David , Cook Sarah , Batten Toby , Granger David , Shah Mittal , O'Donovan Kieran , Nathwani Amit C.
Published: June 2022

7535

Background: NVG-111 is a first in class, humanized, tandem scFv ROR1xCD3 bispecific T cell engager that mediates potent killing of ROR1+ tumours by engaging an epitope on the Frizzled domain of ROR1 and redirecting T cell activity via the CD3 binder. Methods: This phase I/II study is evaluating NVG-111 in patients with relapsed/refractory (R/R) CLL and MCL who have received ≥2 prior systemic therapies and have achieved a stable, or partial response to the last line of therapy. NVG-111 was delivered as continuous intravenous (cIV) infusion over 21 days per cycle, with each patient typically receiving 3 cycles of treatment. The first 3 single patient cohorts were subjected to accelerated dose titration (ADT) over a range of 0.3-30µg/day. Dose-escalation steps in the subsequent, multi-patient, cohorts were determined using a continuous reassessment method with overdose control. The primary endpoints are safety and determination of MTD/RP2D. Secondary objectives are pharmacokinetics, pharmacodynamics, immunogenicity and anti-tumor activity, assessed by multicolor flow cytometry to quantitate minimal residual disease (MRD4). Results: As of January 2022, six patients (all males, median age 60 years) had been enrolled to the study; three into each of the ADT cohorts and the remaining into a 30 µg/day flat dosing cohort. Five patients had CLL, and one had MCL, with all subjects remaining on ibrutinib whilst receiving NVG-111. The most common adverse events were Grade 1 lethargy, headaches, nausea, vomiting and thrombocytopenia. All 3 patients exposed to a flat dose of NVG-111 at 30µg/day suffered Grade 1 cytokine release syndrome (CRS) during week 1 of cycle 1. This did not require tocilizumab or dose interruption except in one patient who developed transient, grade 3 immune effector cell–associated neurotoxicity syndrome-like symptoms (ICANS). CRS or ICANS was not observed in subsequent cycles of treatment at this dose level. Response was observed in all 5 evaluable patients who had completed efficacy assessment after 3 cycles of NVG-111. Amongst these, 2 patients had undetectable MRD in the blood with one being MRD negative in the bone marrow. Dose escalation is ongoing, including exploration of step-up dosing. Conclusions: Early data with NVG-111 shows promising efficacy with a predictable and manageable safety profile. Clinical trial information: NCT04763083.
Real-world analysis of safety and efficacy of CAR T-cell therapy in patients with lymphoma with decreased renal function.
Authors: Mamlouk Omar , Strati Paolo , Feng Lei , Sun Ryan , Steiner Raphael Eric , Nair Ranjit , Flowers Christopher , Ramdial Jeremy L , Saini Neeraj , Srour Samer Ali , Champlin Richard E. , Kebriaei Partow , Nastoupil Loretta J. , Rodriguez Maria Alma , Shpall Elizabeth J. , Nieto Yago , Westin Jason , Neelapu Sattva Swarup , Mandayam Sreedhar , Ahmed Sairah
Published: June 2022

7536

Background: Chimeric antigen receptor T-cell therapy (CART) is approved for treatment of relapsed and refractory large B cell lymphoma (r/r LBCL), however eligibility for patients (pts) treated on clinical trials included normal kidney function (NKF). There is a gap in knowledge regarding the safety and efficacy of CART in pts with reduced kidney function (RKF), despite the prevalence of chronic kidney disease in lymphoma pts. Methods: This is a single-center retrospective analysis of adult pts with r/r LBCL who received CART between 2017-2021. RKF was defined as estimated glomerular filtration rate (GFR) of < 60 ml/min and NKF defined as GFR ≥ 60 ml/min, at time of lymphodepletion chemotherapy (LDC). Increased length of ICU stay define as > 3 days. Kaplan-Meier method used to estimate the time-to-event endpoints including progression free survival (PFS), and overall survival (OS). Results: We identified 210 pts who received CART, of those 169 (80.5%) had NKF and 41(19.5%) had RKF (15-59 ml/min, 27% < 45). Median age of pts was 60 and 63% of RKF pts were older than 60 vs 45% in NKF group (p = 0.03). Median Hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score of pts with RKF was higher than NKF (3 vs. 1, P = 0.004). Pts with RKF had significantly longer ICU length of stay (29.3% vs. 13.6%; p = 0.01). There was no difference in grade 3 hematological toxicity (82.9% vs. 84.5%, p = 0.80) or infection within 30 days of CART (51.2% vs. 37.9%, p = 0.11) between RKF and NKF pts, respectively. CART specific toxicity including grade and frequency of cytokine release syndrome and neurotoxicity was also not related to renal function. After a median follow-up of 22.9 months (95% CI: 21.1-25.6 months), there was no significant difference in PFS and OS when comparing pts with RKF vs. NKF; PFS at 1 year of 31% (19-50%) vs. 33% (26-41%), p = 0.97, and OS at 1 year was 47% (34-67%) vs. 44% (37-57%), p = 0.45, and respectively. However, pts with RKF had a significant increase in non-relapse mortality (NRM) at 3 months (19.5% vs. 8.3%, p = 0.03), and at 6 months (22% vs. 9.5%, p = 0.02), respectively. Conclusions: In this retrospective single center study we observed reassuring durable remission rates in pts with r/r LBCL and RKF who received CART, without significantly different PFS or OS. Interestingly our analysis found that increased ICU length of stay and higher rates of NRM early after CART were associated with RKF. While our data shows RKF does not preclude pts from receiving CART for r/r LBCL, it does suggest that patients with RKF may need closer monitoring and multidisciplinary management.
Safety and clinical activity of belantamab mafodotin with pembrolizumab in patients with relapsed/refractory multiple myeloma (RRMM): DREAMM-4 Study.
Authors: Suvannasankha Attaya , Bahlis Nizar J. , Trudel Suzanne , Weisel Katja , Koenecke Christian , Oriol Rocafiguera Albert , Voorhees Peter M. , Alonso Aránzazu Alonso , Callander Natalie Scott , Mateos Maria-Victoria , Reddy Nishitha , Hakim Shawn , Patel Nashita , Williams Danae , Jewell Roxanne C. , Zhou Xiangdong , Gupta Ira V. , Nooka Ajay K.
Published: June 2022

8018

Background: Belantamab mafodotin (belamaf; BLENREP), a B-cell maturation antigen (BCMA) targeted antibody–drug conjugate approved for adult patients with RRMM, has a multimodal mechanism that eliminates myeloma cells via direct cytotoxicity and a systemic anti-tumor immune response, which may be augmented by an immune checkpoint inhibitor. DREAMM-4 (NCT03848845) assessed safety and clinical activity of belamaf with pembrolizumab (pembro) in RRMM. Methods: This was a Phase I/II, single-arm, open-label study of adults with RRMM after ≥3 lines of therapy (LOT, including anti-CD38 monoclonal antibody, proteasome inhibitor, and immunomodulator). Part 1 established the dose of belamaf 2.5 mg/kg with pembro 200 mg, both IV Q3W up to 35 cycles, for the Part 2 expansion. Primary efficacy endpoint was investigator-assessed overall response rate (ORR, ≥partial response [PR] per IMWG criteria by investigator). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), adverse events (AEs) per NCI-CTCAE v4.03, and pharmacokinetics (PK). Results: This primary analysis of all treated pts (as of Oct 18, 2021) included 34 pts (6 in Part 1 and 28 in Part 2). In both parts, median prior LOT was 5 (range 3–13); 10 pts (29%) had high-risk cytogenetics and 9 (26%) had extramedullary disease. ORR was 47%, with most responses (10/16 pts) ≥ very good PR (VGPR, Table). Median follow-up was 14.7 months (mo); median (95% CI) DoR was 8.0 (2.1–not reached) mo; median PFS was 3.4 (1.4–5.6) mo. Most pts had ≥1 AE (any grade [Gr]: 97%; Gr ≥3: 74%) and treatment-related AE (TRAE, any Gr: 97%; Gr ≥3: 65%). Most common (≥35%) AEs were keratopathy (any Gr: 76%; Gr ≥3: 38%), vision blurred (any Gr: 38%; Gr ≥3: 0%), and thrombocytopenia (any Gr: 35%; Gr ≥3: 29%). AEs led to dose delays (65%) and dose reductions (32%), but not discontinuation. Nine pts had a serious AE (SAE); 4 pts had ≥1 SAE related to study treatment. Two pts had immune-related AEs of Gr 1 (gout and autoimmune hypothyroidism). Preliminary PK and soluble BCMA data were consistent with single-agent belamaf therapy. Conclusions: Belamaf + pembro demonstrated a favorable ORR compared with single-agent belamaf in heavily pre-treated RRMM. No new TRAEs were identified; AE frequency and severity were similar to single-agent belamaf. Correlative biomarker studies are ongoing. Clinical trial information: NCT03848845. [Table: see text]
Time to response, duration of response, and patient-reported outcomes (PROs) with daratumumab (DARA) plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): Subgroup analysis of the phase 3 MAIA study.
Authors: Facon Thierry , Kumar Shaji , Plesner Torben , Moreau Philippe , Bahlis Nizar J. , Goldschmidt Hartmut , O'Dwyer Michael , Perrot Aurore , Venner Christopher P. , Weisel Katja , Mace Joseph R. , Raje Noopur S. , Tiab Mourad , Macro Margaret , Frenzel Laurent , Leleu Xavier , Pei Huiling , Borgsten Fredrik , Usmani Saad Zafar
Published: June 2022

8044

Background: In the phase 3 MAIA study, adding DARA to Rd improved progression-free survival (primary endpoint), overall survival, duration of response, and PROs in transplant-ineligible pts with NDMM. We report a MAIA subgroup analysis of time to response, duration of response, and PROs. Methods: Transplant-ineligible pts with NDMM received 28-day cycles of Rd (R 25 mg PO on Days 1-21; d 40 mg PO QW) ± DARA (16 mg/kg IV QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter) until disease progression or unacceptable toxicity. Secondary endpoints included time to response and duration of response. PROs were measured using the EORTC QLQ-C30, with treatment effects assessed via mixed-effects model with repeated measures. Results: In total, 368 pts were assigned to the D-Rd group and 369 pts to the Rd group; 162 (44%) D-Rd pts and 142 (38%) Rd pts had renal impairment (defined as baseline CrCl ≤60 mL/min). At a 56.2-mo median follow-up, median times to very good partial response or better (≥VGPR) and complete response or better (≥CR) were shorter with D-Rd vs Rd in the overall study population and in the subgroups of pts with and without renal impairment (Table). Among pts who achieved ≥CR or partial response or better (≥PR), higher proportions of D-Rd vs Rd pts had not experienced disease progression at 48 mo (Table). Among pts with renal impairment, greater improvements from baseline in pt-reported pain, fatigue, and nausea and vomiting symptom scores were observed with D-Rd vs Rd across most timepoints; a notably greater meaningful reduction in pain symptom score was seen with D-Rd vs Rd as early as Cycle 6 Day 1 (least squares mean change from baseline, −14.9 vs −7.0; P=0.0241). Analyses for additional pt subgroups will be presented. Conclusions: In transplant-ineligible pts with NDMM, D-Rd showed more rapid deep responses as well as more durable responses vs Rd, regardless of renal function. Improvements in pt-reported symptoms were generally greater with D-Rd vs Rd in pts with renal impairment. Our results support the use of D-Rd in transplant-ineligible pts with NDMM. Clinical trial information: NCT02252172. [Table: see text]
Comparison of quality of life in patients randomized to high-dose once daily (QD) thoracic radiotherapy (TRT) with standard twice daily (BID) TRT in limited stage small cell lung cancer (LS-SCLC) on CALGB 30610 (Alliance, Sub-study CALGB 70702).
Authors: Ganti Apar Kishor , Dueck Amylou C. , Fruth Briant , Rimner Andreas , Waqar Saiama Naheed , Mix Michael D , Petty William J. , Bogart Jeffrey A
Published: June 2022

8504

Background: The CALGB 30610 trial demonstrated that 70Gy QD TRT was not associated with a superior overall survival compared to standard BID 45Gy TRT in limited stage small cell lung cancer. Since both arms appeared to provide similar clinical benefit, other factors such as quality of life may help oncologists decide on the best treatment approach for their patients. The present analysis was conducted to compare patients’ quality of life between these regimens in terms of their physical symptoms, physical functioning and psychological state. Methods: In the CALGB 30610 planned sub-study CALGB 70702, patients were administered the FACT-L, FACT Trial Outcome Index-Lung Cancer (FACT-L TOI), FACT-Esophageal Cancer Eating and Swallowing Indices, ECOG Acute Esophagitis Scale, Hospital Anxiety and Depression Scale (HADS), the EQ-5D at baseline and a single item assessing difficulty swallowing at baseline, 3, 5, 7, 12, 26, and 52 weeks after starting radiation therapy. Patients were also asked to assess treatment inconvenience at these time points. The primary endpoints of CALGB 70702 were FACT-L TOI and FACT eating and swallowing subscales at 12 weeks. Mean changes from baseline were compared between arms using general linear mixed models. Results: 417 patients consented to participate in the patient-reported outcomes substudy. The completion rate of the questionnaires was 87% at baseline and 71% at week 52. The FACT-L total score mean worsening was significantly less in the QD arm compared to the BID arm at week 3 (-1.0 vs -7.0; P=.003), and marginally less at week 5 (-5.3 vs -11.0; P=.06). The FACT-L TOI mean worsening was significantly less in the QD arm than in the BID arm at week 3 (-2.9 vs -7.6; P=.003) and greater at week 12 (-7.6 vs -2.8; P=.03). The QD arm also had a lesser EQ-5D index mean worsening at 3 weeks (-0.04 vs 0.03; P=.002). Mean increase in the acute esophagitis score (1.06 vs 2.89; P<.001) and difficulty swallowing (0.39 vs 1.14; P<.001) were significantly greater in the BID arm at week 3. Mean worsening in HADS anxiety was significantly less in the QD arm at week 5 (-1.99 vs -0.95; P=.03). There were no other significant differences at the remaining timepoints between the two arms. Across visits on the QD arm, patients felt that treatment was inconvenient at 26% (96/376) assessments, compared to 33% (116/352) in the BID arm (chi-sq P=.03). Conclusions: Both radiation regimens were well tolerated. However, the QD arm had better quality of life scores at week 3 and was perceived to be less inconvenient. Clinical trial information: NCT00632853.