bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of vitamin D deficiency and COVID-19 diagnosis in patients with breast or prostate cancer using electronic medical records.
Authors: Galaznik Aaron , Rusli Emelly , Wing Vicki , Jain Rahul , Diamond Sheila , Fajgenbaum David
Published: June 2021

6589

Background: While patients with cancer are known to be at increased risk of infection in part due to the immunocompromising nature of cancer treatments, recent data indicate a particularly high risk for COVID-19 infection and poor outcomes (Wang et al., 2020). A recent study (Meltzer et al., 2020) demonstrated Vitamin D deficiency may increase risk of COVID-19 infection, and a small randomized controlled trial in Spain reported significant improvement in mortality among hospitalized patients treated with calcifediol. Vitamin D deficiency has been reported in two leading causes of cancer deaths: breast and prostate. In this study, we performed a retrospective cohort analysis on nationally representative electronic medical records (EMR) to assess whether Vitamin D deficiency affects risk of COVID-19 among these patients. Methods: Patients with breast (female) or prostate (male) cancer were identified between 3/1/2018 and 3/1/2020 from EMR data provided pro-bono by the COVID-19 Research Database ( covid19researchdatabase.org ). Patients with an ICD-10 code for Vitamin D deficiency or < 20ng/mL 20(OH)D laboratory result within 12 months prior to 3/1/2020 were classified as Vitamin D deficient. COVID-19 diagnosis was defined using ICD-10 codes and laboratory results for COVID-19 at any time after 3/1/2020. Logistic regressions, adjusting for baseline demographic and clinical characteristics, were conducted to estimate the effect of Vitamin D deficiency on COVID-19 incidence in each cancer cohort. Results: A total of 16,287 breast cancer and 14,919 prostate cancer patients were included in the study. The average age was 68.9 years in the breast cancer cohort and 73.6 years in the prostate cancer cohort. The breast cancer cohort consisted of 85% Whites, 13% Black or African Americans, and less than 5% of other races. A similar race distribution was observed in the prostate cancer cohort. Unadjusted analysis showed the risk of COVID-19 was higher among Vitamin D deficient patients compared to non-deficient patients in both cohorts (breast: OR = 1.60 [95% C.I.: 1.15, 2.20]; prostate: OR = 1.59 [95% C.I.: 1.08, 2.33]). Similar findings were observed when assessed in subgroups of patients with newly diagnosed cancer in the dataset, as well as after adjusting for baseline characteristics. Conclusions: Our study suggests breast and prostate cancer patients may have an elevated risk of COVID-19 infection if Vitamin D deficient. These results support findings by Meltzer et al., 2020 demonstrating a relationship between Vitamin D deficiency and COVID-19 infection. While a randomized clinical trial is warranted to confirm the role for Vitamin D supplementation in preventing COVID-19, our study underscores the importance of monitoring Vitamin D levels across and within cancer populations, particularly in the midst of the global COVID-19 pandemic.
Comparative study of prevalence and costs of depression and anxiety among elderly cancer patients.
Authors: DaCosta Byfield Stacey , Tanudtanud Kae , Barrientos John Rich , Lasquite Kiesha Mae , Catlett Kierstin
Published: June 2021

6595

Background: Depression and anxiety are common among cancer patients and can worsen outcomes. We studied the occurrence of depression and anxiety in three common cancers to investigate whether healthcare costs were greater for cancer patients with two mental health disorders (MHD), depression and anxiety, compared to patients without MHD. Methods: This retrospective analysis used deidentified medical and pharmacy claims from a large national U.S. health insurer. Patients were Medicare Advantage enrollees ≥65 years diagnosed with breast, colorectal, or prostate cancer and continuously enrolled from 1/2018–12/2019. We determined statistically whether the annual prevalence of the two MHDs varied by cancer types. Total costs and costs exclusive of MHD-related expenses in five sub-categories were compared: inpatient, emergency room, non-inpatient medical, professional, and pharmacy. Costs from 2019 claims were presented as per-patient per-month (PPPM). Direct depression- and anxiety-related costs were from claims with depression/anxiety diagnoses or drugs. The impact of MHDs on 2019 healthcare spending was examined using multiple linear regression, controlling for demographic and clinical characteristics. LASSO was used for variable selection. Mann-Whitney U tests compared differences in costs by service types between patients with and without MHDs. Results: Of 19,304 study patients, 8,916 (46%) had coexisting depression or anxiety: (i) 4% depression only; (ii) 27% anxiety only; (iii) 7% depression and anxiety; and (iv) 8% were on antidepressant without MHDs diagnoses. There were significant differences in the rates of MHDs between the three cancer groups, with the highest frequency in breast cancer ( breast vs colorectal. 56% vs 49%, p < 0.0005 ; breast vs prostate. 56% vs 38%, p < 0.0005; colorectal vs prostate. 49% vs 38%, p < 0.0005). After excluding the MHDs-related costs (PPPM mean = $44), the monthly spending was 54% higher for patients with MHDs ($2,184 MHDs vs. $1,406 non-MHDs). After adjusting for covariates, the PPPM costs were 23%–58% higher for the MHD-cohort vs. the non-MHD cohort for each cancer type ( non-MHD vs. with depression only, CI 13%–34%, p < 0.0001; non-MHD vs. with anxiety only, CI 40%-52%, p < 0.0001; non-MHD vs. with depression and anxiety, CI 48%-70%, p < 0.0001; non-MHD vs. with antidepressant only, CI 28%-45%, p < 0.0001). Higher costs in MHD-cohort were observed in all cost categories (p < 0.0001). Conclusions: We found high prevalence of MHDs in patients diagnosed with cancer. Analyses showed that total spending was significantly higher in individuals with cancer and MHD for all cost categories. Explanations for higher costs are unclear, as costs remain high even after adjusting for MHD-related care costs. Research on specific healthcare services driving higher costs and the risk factors for depression and anxiety is needed to address broader MHDs to improve cancer care.
Update of a phase II, multicenter study of high-dose chemotherapy with autologous stem cell transplant followed by maintenance romidepsin for T-cell lymphoma.
Authors: Khan Niloufer , Khimani Farhad , Shustov Andrei R. , Shadman Mazyar , Ruan Jia , Moskowitz Alison J. , Straus David J. , Kumar Anita , Sauter Craig Steven , Zelenetz Andrew David , Noy Ariela , Shah Gunjan L. , Matasar Matthew J. , Drullinsky Pamela , Hamilton Audrey M. , Drill Esther N. , Van Besien Koen , Giralt Sergio , Horwitz Steven M. , Dahi Parastoo
Published: June 2021

7533

Background: Peripheral T-cell lymphomas (PTCL) have suboptimal outcomes with conventional chemotherapy. Autologous hematopoietic stem cell transplant (AHCT) is a therapeutic strategy for patients in first complete or partial remission (CR1 or PR1), with median progression-free survival (PFS) after AHCT of 36-48% by intent to treat (d’Amore et al JCO 2012, Reimer et al JCO 2009). Romidepsin (romi) is a histone deacetylase inhibitor approved for treatment of relapsed/refractory T-cell lymphoma. We present updated data of the first multicenter study to evaluate PFS of patients (pts) receiving maintenance therapy with romi after AHCT. Methods: This was a phase 2, open-label, investigator-initiated study (expected PFS 45%, desired PFS 70%; success achieved if 15 or more pts out of 25 were progression-free at 2 years post-AHCT). 26 pts transplanted in CR1 or PR1 were evaluable for the primary endpoint of 2-year PFS (Cohort 1, Table). An exploratory cohort (Cohort 2, n=7) enrolled pts either transplanted ≥ CR/PR2 (n=5) or with high risk histologies (n=2). Pts underwent AHCT with carmustine, etoposide, cytarabine and melphalan (BEAM) conditioning. Maintenance romi 14 mg/m2 started days 42-80 post AHCT; every other week through 6 mon, every 3 weeks through 1 year and every 4 weeks through 2 years post AHCT. PFS was estimated by Kaplan-Meier. Results: 47 pts consented; 13 did not receive romi (no AHCT, n=2; relapse before romi, n=3; cardiac comorbidity, n=3, patient declined, n=5). 1 consented pt did not have PTCL. 15 out of the first 25 pts in Cohort 1 were progression free after 2 years; median follow up of 31 mon (21 - 36 mon). Estimated 2-year PFS was 62% (45-83%, 95% CI); median PFS 30 mon (12.0- NA, 95% CI). In Cohort 2, estimated 2-year PFS was 43% (18 – 100, 95% CI); median follow up of 30 mon (range, 24 – 37 mon); median PFS 14 mon (5 – NA, 95% CI). Across cohorts, 5 pts required dose reduction. The most common toxicities (≥10% of pts, all grades) were fatigue (n=24, 73%), decreased platelets (n=16, 48%) and anemia (n=16, 48%). Conclusions: While the study did not meet its desired primary efficacy endpoint, maintenance romi was well-tolerated with an estimated 2-year PFS of 62%, greater than historical data. A larger, randomized study would be needed to determine the superiority of this approach. Clinical trial information: NCT01908777. [Table: see text]
Effects of weekly selinexor, bortezomib, dexamethasone (XVd) versus standard twice weekly bortezomib and dexamethasone (Vd) on RAS-mutated previously treated multiple myeloma (MM).
Authors: Walker Christopher James , Li Shirong , Chai Yi , Shah Jatin J. , Shacham Sharon , Lentzsch Suzanne , Landesman Yosef
Published: June 2021

8027

Background: Activating mutations of the RAS genes NRAS, KRAS, and HRAS ( RASmut) occur in up to 50% of MM and portend poor survival and high recurrence rates. MM cells with RASmut are susceptible to inhibition of germinal center kinase (GCK), resulting in IKAROS degradation independent of cereblon (CRBN). Selinexor is a selective inhibitor of nuclear export (SINE) compound that can induce IKAROS degradation through CRBN-independent pathways to overcome immunomodulatory drug resistance. We explored the benefit of selinexor treatment for pts with RASmut MM. Methods: In the randomized BOSTON study, pts with MM after 1-3 therapies received weekly XVd or twice weekly Vd. In the single-arm STORM study pts with penta-treated, triple class refractory MM were treated with twice weekly Xd. Both treatment regimens are now FDA approved. Mutations were assessed post-hoc by exome sequencing of 119 and 52 pts from BOSTON and STORM, respectively. Pts were considered RASmut if their MM had NRAS, KRAS or HRAS mutations in codons 12, 13 or 61. Results: There were 54 pts (45%) with RASmut in BOSTON (XVd = 26, Vd = 28), and 17 (33%) in STORM. In BOSTON, pts with RASmut MM treated with XVd had significantly longer progression-free survival (PFS) than those treated with Vd (median [med] = 12.9 vs 6.7 months [mo], hazard ratio [HR] = 0.48 [95% CI 0.24-0.97], p = 0.039). For pts treated with Vd, those with RASmut had significantly shorter overall survival (OS) compared to RASwild-type (WT) (med = 16.8 mo vs not reached [NR], HR = 2.87 [95% CI 1.03-7.99], p = 0.035). PFS was not significantly different (med = 6.74 vs 9.82 mo, HR = 1.64 [95% CI 0.88-3.07], p = 0.122). Amongst pts on XVd, there was no difference in survival between RASmut and RASWT pts (PFS: med = 12.8 vs 12.9 mo, HR = 1.08 [95% CI 0.52-2.26], p = 0.83; OS: med = NR vs NR, HR = 0.94 [95% CI 0.36-2.45], p = 0.91). In STORM, pts with RASmut had shorter OS compared to RASwt pts (med = 6.1 vs NR, HR = 2.05 [95% CI 1.22-5.19], p = 0.010). Preliminary studies to explore the mechanisms of action related to RASmut MM sensitivity to XVd demonstrated that selinexor treatment in vitro leads to downregulation of GCK. Conclusions: Despite typically having the worst outcomes, pts with RASmut MM had a similar benefit from XVd as RASWT MM, showing that the XVd combination can overcome RASmut. Mechanistically, selinexor induced down regulation of GCK and enhanced killing of RASmut MM cells. With a manageable safety profile, the XVd regimen could provide a viable treatment option to improve survival of pts with MM with RAS mutations. Clinical trial information: NCT03110562. [Table: see text]
Isatuximab plus carfilzomib and dexamethasone in patients with relapsed multiple myeloma according to prior lines of treatment and refractory status: IKEMA subgroup analysis.
Authors: Hajek Roman , Moreau Philippe , Augustson Bradley , Castro Nelson , Pika Tomas , Delimpasi Sosana , de La Rubia Javier , Maiolino Angelo , Reiman Tony J. , Kryuchkova Irina , Martinez-Lopez Joaquin , Martin Thomas G. , Mikhael Joseph , Yong Kwee , Risse Marie-Laure , Asset Gaëlle , Marion Sylvia , Dimopoulos Meletios A.
Published: June 2021

8034

Background: Patients (pts) with multiple myeloma (MM) often relapse and become refractory to successive lines of therapy, warranting better treatment options. The Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) plus carfilzomib and dexamethasone (Kd) significantly improved progression-free survival (PFS) compared with Kd in pts with relapsed MM (RMM) (HR 0.53; 99% CI 0.32–0.89; P= 0.0007). We evaluated the efficacy and/or safety of Isa-Kd by number of prior lines of therapy (1 vs > 1) and refractoriness to lenalidomide (Len) or bortezomib (Bor). Methods: Pts were randomized (3:2) to Isa-Kd (n = 179) or Kd (n = 123). Isa (10 mg/kg IV) was given weekly for 4 weeks, then every 2 weeks. K (20 mg/m² days 1-2, then 56 mg/m²) was given twice-weekly 3 of 4 weeks, and d (20 mg) twice-weekly. The primary endpoint was PFS; key secondary endpoints were very good partial response or better (≥VGPR), minimal residual disease negativity (MRD-), and complete response (CR) rates. Results: Of the 302 randomized pts, 44.7% had 1 prior line, 55.3% had > 1 prior line, 32.8% were Len-refractory, and 30.1% were Bor-refractory. PFS was improved with Isa-Kd vs Kd in pts who received 1 prior line and > 1 prior line, as well as in pts refractory to Len, Len at last regimen, Bor, or Bor at last regimen (Table). The addition of Isa to Kd improved depth of response (≥VGPR, MRD-, and CR rates) in all subpopulations analyzed by prior treatment. Grade ≥3 treatment-emergent adverse events (TEAEs) were generally similar between the prior line subgroups (77.2% [Isa-Kd] vs 64.8% [Kd], 1 prior line; 76.5% [Isa-Kd] vs 69.1% [Kd], > 1 prior line) and the overall safety population (76.8% [Isa-Kd] vs 67.2% [Kd]). Serious AEs were 62.0% vs 48.1% in the 1 prior line subgroup, and 57.1% vs 64.7% in the > 1 prior line subgroup; TEAEs leading to discontinuations were 8.9% vs 11.1%, 1 prior line and 8.2% vs 16.2%, > 1 prior line. Conclusions: The addition of Isa to Kd improved PFS and depth of response, irrespective of prior lines of therapy or refractory status, consistent with the benefit observed in the overall IKEMA study population. Isa-Kd had a manageable safety profile regardless of number of prior lines. Isa-Kd is a potential new treatment option for pretreated pts with RMM. Clinical trial information: NCT03275285. [Table: see text]
Melflufen plus dexamethasone (dex) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) exposed/refractory to prior alkylators: A pooled analysis of the O-12-M1 and HORIZON studies.
Authors: Rodríguez-Otero Paula , Mateos Maria-Victoria , Oriol Albert , Larocca Alessandra , Blade Joan , Cavo Michele , Leleu Xavier , Nadeem Omar , Hiemenz John W. , Hassoun Hani , Touzeau Cyrille , Alegre Adrian , Paner Agne , Maisel Christopher , Mazumder Amitabha , Raptis Anastasios , Thuresson Marcus , Harmenberg Johan , Harlin Olof , Richardson Paul G.
Published: June 2021

8048

Background: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that leverages aminopeptidases and rapidly releases alkylating agents inside tumor cells. Melflufen has a mechanism of action distinct from other alkylating agents (Slipicevic et al. AACR 2020. Abs. 1843). In the O-12-M1 (NCT01897714) and HORIZON (OP-106; NCT02963493) studies, melflufen plus dex showed meaningful efficacy and a clinically manageable safety profile in pts with RRMM (Richardson et al. Lancet Haematol. 2020;7:5; Richardson et al. J Clin Oncol. 2020;Dec 9 [Epub]). This pooled analysis examines pts from these studies exposed to prior alkylators. Methods: Both the O-12-M1 and HORIZON studies included pts with RRMM who received ≥ 2 prior lines of therapy (LoTs) and had a primary endpoint of overall response rate (ORR). Secondary endpoints included progression-free survival (PFS) and safety. Data from the 2 studies were pooled and analyzed according to previous exposure and refractoriness to alkylators before study entry. Refractoriness to prior alkylator therapy was defined as disease that failed to achieve a minimal response or progressed while on therapy, or within 60 d of last therapy. Results: Of 202 pts (HORIZON: n = 157, cutoff January 14, 2020; O-12-M1: n = 45, cutoff October 29, 2019), 178 (88%) had been exposed to alkylators in ≥ 1 prior LoT (see Table for subgroups). Pts exposed and refractory to alkylators in ≥ 2 LoTs had the highest number of pts refractory to an alkylator in the last LoT (61%), and 82% were refractory to an alkylator within 12 mo of study entry. Meaningful response rates were seen in all subgroups, except for pts who were exposed and refractory to alkylators in ≥ 2 prior LoTs (see Table). PFS trended toward being shorter with higher exposure and refractoriness to prior alkylators. Results should be interpreted with caution due to limited pt numbers. Grade 3/4 adverse events (AEs) were similar between pts exposed to prior alkylators (O-12-M1: 85%; HORIZON: 89%) and the overall population (O-12-M1: 84%; HORIZON: 89%). The most common AEs were hematologic, but were mostly reversible and clinically manageable. Nonhematologic AEs were infrequent and primarily grade 1/2. Conclusions: Melflufen in combination with dex showed meaningful efficacy and a clinically manageable safety profile in pts with RRMM exposed/refractory to prior alkylators. Clinical trial information: NCT02963493 and NCT01897714. [Table: see text]
Two-year follow-up of single PD-1 blockade in neoadjuvant resectable NSCLC.
Authors: Gao Shugeng , Li Ning , Gao Shunyu , Xue Qi , Wang Shuhang , Lv Fang , Zhao Liang , Zhang Fan , Zhao Ziran , Su Kai , Tan Fengwei , Ling Yun , Wang Zhijie , Tang Wei , Ying Jianming , Wu Ning , Wang Jie , He Jie
Published: June 2021

8522

Background: Early stage non-small-cell lung cancer (NSCLC) could benefit from anti-programmed cell death-1 (PD-1) monotherapy; however, the survival profiles remain to be disclosed. Here, we presented the two-year follow-up outcomes from a phase 1b study of sintilimab, an anti-PD-1 inhibitor in the neoadjuvant setting of NSCLC. Methods: Treatment-naive pts with resectable NSCLC (stage IA–IIIB) received two cycles of sintilimab followed by surgical resection. Postoperative treatment of sintilimab was at the discretion of investigator. The primary endpoint was AE, and key secondary endpoints included major pathological response (MPR), disease free survival (DFS) rate of 1 year and 2 years, and overall survival (OS) rate of 2 years. Results: Among 40 enrolled pts, 36 (90%) underwent R0 resection and were included in the R0 resection population. By data cutoff (January 20, 2021), the median follow-up for DFS and OS for all the enrolled pts was 23.9 (IQR 20.5–24.4) months and 26.4 (IQR 24.2–29.0) months. A total of 12 (33.3%) pts experienced relapse, and 6 pts died. The 1-yr and 2-yr DFS rate was 91.7%/73.3%. The 2-yr OS rate for overall population and R0 population was 87.5%/91.7%, respectively. In the R0 resection population, the median DFS and OS were both not reached. Superior 2-year DFS rates were observed in pts who achieved MPR (MPR vs. Non-MPR: 86.7% vs. 63.8%). DFS of pts with non-squamous cell carcinoma tended to be shorter than that of pts with squamous cell carcinoma (HR 2.71 [95%CI 0.67–11.0], p=0.1479). Pts with tumor mutation burden (TMB) ≥10 mutations/Mb and PD-L1 tumor proportion score (TPS)≥50% tended to have a better 2-yr DFS rate compared to those with TMB<10 and TPS<50. [table] For the post-hoc event free survival (EFS) analysis, the same trend was observed with DFS among different subgroups, and patients with TMB ≥10 mutations/Mb had a significant improved EFS (HR 0.125[95% CI 0.02,1.03], P=0.0222). Conclusions: Anti-PD-1 monotherapy emerged to be a promising neoadjuvant therapeutic strategy for resectable NSCLC with improved clinical outcomes. MPR could serve as a surrogate efficacy biomarker in this setting. Clinical trial information: ChiCTR-OIC-17013726. [Table: see text]
Statewide rates of adjuvant checkpoint inhibitor use after definitive chemoradiation for stage III non-small cell lung cancer.
Authors: Bryant Alex K. , Yin Huiying , Schipper Matthew J. , Paximadis Peter Alexander , Boike Thomas Pence , Bergsma Derek P. , Movsas Benjamin , Ajlouni Munther Isa , Dess Robert Timothy , Mietzel Melissa A. , Kendrick Randi , Seferi Merita , Dominello Michael M. , Matuszak Martha , Jagsi Reshma , Hayman James , Pierce Lori J. , Jolly Shruti
Published: June 2021

8523

Background: In the landmark PACIFIC trial, adjuvant durvalumab after definitive chemoradiation for unresectable stage III non-small-cell lung cancer (NSCLC) produced a 11% absolute overall survival benefit at two years compared to placebo, and the US Food and Drug Administration approved durvalumab for this indication in February 2018. We investigated the real-world use of adjuvant durvalumab and other immune checkpoint inhibitors (ICI) in a contemporary cohort of patients. Methods: We identified patients with unresectable stage III (AJCC 8th edition) NSCLC treated with definitive chemoradiation from February 2018 to March 2020 from a statewide radiation oncology quality consortium, representing a mix of community (n=22 centers, 336 patients) and academic practice settings (n=5 centers, 64 patients) across the state of Michigan. Use of adjuvant durvalumab or other ICI (atezolizumab, nivolumab, or pembrolizumab) was ascertained at the time of routine three- or six-month follow-up after completion of chemoradiation. Baseline characteristics of patients treated with or without adjuvant ICI were compared with the Chi-squared test for categorical variables and a two-sided t-test for continuous variables. Results: Of 400 patients with unresectable stage III NSCLC treated with definitive chemoradiation, 268 (67%) received adjuvant ICI. Of these, the majority received durvalumab (86%) followed by pembrolizumab (7.5%) and nivolumab (6.0%). The proportion of patients receiving ICI remained stable throughout the study period with no discernable time trends. Eight-five percent of white patients received ICI compared with 77% of black patients (p=0.04), but there were no differences in gender (54.5% male in ICI vs 52.3% no ICI), current smoking (42.2% ICI vs 37.9% no ICI, p=0.68), number of comorbidities (29.5% with 3 or more comorbidities in ICI vs. 26.5% in no ICI, p=0.86), baseline oxygen use (8.9% ICI vs 10.6% no ICI, p=0.59), age (median 66.4 years [IQR 60.3-73.4] for ICI vs. 66.9 years [IQR 61.1-72.2] no ICI, p=0.89), treatment at an academic center (16.0% ICI vs 15.9% no ICI, p=0.97), or ECOG performance status (59.3% ECOG 0 in ICI vs 62.8% no ICI). Conclusions: In a broad range of academic and community-based practices across a state including 27 sites, only two-thirds of potentially eligible stage III NSCLC patients received adjuvant durvalumab or other ICI agents despite a proven overall survival benefit. Receipt of ICI was not strongly associated with baseline demographic or comorbidity variables. Further work will seek to clarify the patient-level reasons behind non-initiation of adjuvant ICI.
Noninvasive identification of emergent mutations following cytotoxic therapy for lung cancer.
Authors: Moding Everett James , Hui Angela B. , Murciano-Goroff Yonina R. , Nabet Barzin , Schultz Andre , Qiao Yawei , Li Bob T. , Lin Steven H. , Alizadeh Ash A. , Diehn Maximilian
Published: June 2021

8533

Background: Lung cancer is the leading cause of cancer death world-wide, and chemotherapy and radiation remain backbones of therapy for patients with locoregionally advanced and metastatic disease. However, the genetic mechanisms that mediate resistance to chemotherapy and radiation are largely unclear due to a lack of available tissue at the time of relapse. We hypothesized that circulating tumor DNA (ctDNA) analysis could identify emergent mutations after chemotherapy and radiation that may lead to treatment resistance. Methods: To identify emergent mutations at the time of progression following an initial response to chemotherapy and/or radiation therapy for lung cancer, we utilized CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) to analyze plasma samples and matched leukocytes collected pre-treatment and at the time of relapse. We analyzed a targeted panel enriched for lung cancer drivers and recurrently mutated genes for 27 patients treated with chemoradiation therapy for locoregionally advanced lung cancer. In addition, we performed ultra-deep whole exome sequencing ( > 2000X deduped depth) of pre-treatment and relapse cell-free DNA for 5 patients treated with combination chemotherapy for metastatic lung cancer. Functional enrichment analysis was performed on emergent mutation gene lists to identify significantly enriched pathways. Results: We identified emergent variants in 6 out of 27 patients using targeted sequencing after chemoradiation therapy. Emergent mutations after chemoradiation were enriched for plasma membrane adhesion molecules such as PCDH17, PCDH10, and FAT3 (adjusted P = 0.03). Using ultra-deep whole exome sequencing, we observed emergent mutations in 3 out of 5 patients treated with combination chemotherapy. After combination chemotherapy, there was a trend towards enrichment in mutations in ATP-binding cassette transporters, including ABCA13 and ABCB4 (adjusted P = 0.057). Notably, there were no recurrent emergent mutations within our cohort. Conclusions: Our results suggest that ultra-deep whole exome sequencing can non-invasively identify emergent mutations at the time of progression. Resistance to cytotoxic therapy is likely multi-factorial and analysis in expanded cohorts will be helpful to identify recurrently mutated pathways that may contribute to disease progression after an initial response to therapy.
Early detection of lung cancer with an incidental lung nodule program (ILNP).
Authors: Smeltzer Matthew , Liao Wei , Meadows-Taylor Meghan , Faris Nicholas , Fehnel Carrie , Goss Jordan , Williams Sara C. , Akinbobola Olawale , Pacheco Alicia , Epperson Amanda , Luttrell Joy , McCoy Denise , Tokin Keith , Optican Rob , Wright Jeffrey , Robbins Edward Todd , Satpute Shailesh R. , Harris Parker , Ray Meredith , Osarogiagbon Raymond U.
Published: June 2021

8553

Background: Lung cancer early detection improves survival, but risk-based low-dose CT screening (LDCT) only identifies a minority of patients. We implemented an ILNP in a community healthcare system, and evaluated its risks and benefits. Methods: Patients with lung lesions on routinely-performed radiologic studies were flagged by radiologists and triaged using evidence-based guidelines. We tracked demographics, clinical characteristics, procedures, complications, and health outcomes. We analyzed ILNP subjects’ eligibility for LDCT by National Lung Screening Trial (NLST), Center for Medicaid Services (CMS), NEderlands Leuvens Screening ONderzoek (NELSON), National Comprehensive Cancer Network (NCCN) Risk Groups 1 and 2 (screening recommended), NCCN Risk Group 3 (screening not currently recommended), and US Preventive Services Task Force (USPSTF) criteria from 2013 and 2020. Statistical analysis used the chi-square test and Kaplan Meier method. Results: From 2015-2020, 13,710 patients were evaluated in the ILNP program: median age, 64 years; 42% male; 65% White, 29% Black; 667 (4.9%) were diagnosed with lung cancer. Lung cancers diagnosed from ILNP were 39% adenocarcinoma / 20% Squamous Cell with clinical stage distribution 49% I, 8% II, 17% III, and 16% IV. 832 (6.1%) had invasive diagnostic testing- CT-guided biopsy (50%), bronchoscopy (30%), and/or EBUS (26%); 11% of the 832 had >1 invasive diagnostic test. The most common complications from invasive testing were pneumothorax and chest tube placement. Only 11%-20% of all ILNP patients would have been eligible for LDCT. In ILNP patients diagnosed with lung cancer, only 33% were eligible for screening by NLST criteria; the proportion increased substantially when USPSTF 2020 or NCCN Group 2 criteria were applied (Table). Compared to NLST, NCCN Group 2 criteria increased screening eligibility among cancer patients by 22% (from 33% to 55%), while only increasing screening eligibility by 6% (from 8% to 14%) in non-cancer patients. Aggregate 1-year and 3-year survival rates for lung cancer patient diagnosed through ILNP were 76% (95% CI: 73, 80) and 64% (95% CI: 59, 69). Conclusions: The ILNP identified early-stage lung cancer more frequently than most LDCT programs, with promising survival rates. The majority of subjects with lung cancer were not eligible for LDCT, we still need to optimize risk-based screening criteria. Even with new, expanded criteria for LDCT, structured ILNP is necessary to expand early detection of lung cancer.[Table: see text]
Comprehensive molecular profiling of pleural mesothelioma according to histologic subtype.
Authors: Dagogo-Jack Ibiayi , Madison Russell , Mata Douglas A. , Schrock Alexa Betzig , Janovitz Tyler , Decker Brennan , Huang Richard S.P. , Lin Douglas I. , Killian Jonathan Keith , Ramkissoon Shakti H. , Gjoerup Ole , Danziger Natalie , Venstrom Jeffrey Michael , Alexander Brian M. , Ross Jeffrey S.
Published: June 2021

8555

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with limited therapeutic options. Immunotherapy has emerged as an effective therapeutic strategy, particularly in the non-epithelioid MPM subgroup. An improved understanding of the molecular profile of MPM may inform targeted therapeutic approaches and provide insights into factors underlying differential sensitivity to therapies. Methods: We performed comprehensive genomic profiling of MPMs from 980 patients, with histologic subtyping on a subset (n = 340; n = 235 epithelioid, n = 48 sarcomatoid, n = 57 biphasic). Analyses included quantifying tumor mutational burden (TMB), assessing microsatellite instability (MSI), and evaluating PD-L1 expression (Dako 22C3). Results: Median TMB of MPM was 1.74 (0.87-2.61) mutations per megabase (mut/mb). Median TMB was comparable for non-epithelioid (biphasic, sarcomatoid) vs epithelioid MPM (1.25 mut/mb vs 1.25 mut/mb, p = 0.43). In the overall cohort, inactivating alterations in the following genes were most prevalent: CDKN2A (49%), BAP1 (44%), CDKN2B (42%), MTAP (35%), and NF2 (33%). MTAP loss co-occurred with CDKN2A and CDKN2B loss in > 99% and 94% of cases, respectively. MTAP loss was observed in 28% of epithelioid vs 46% of non-epithelioid MPMs (p = 0.03). BAP1 alterations were detected in 51% of epithelioid vs 36% of non-epithelioid MPMs (p = 0.81). PD-L1 expression was assessed in 308 MPMs, among which 153 (49%) had PD-L1 ≥1%, including 35 (11%) with PD-L1 ≥50%. Among 164 specimens that underwent histologic subtyping and PD-L1 evaluation, PD-L1 was expressed in 46 (71%) non-epithelioid MPMs compared to 49 (51%) epithelioid MPMs (p = 0.03). Given the high prevalence of alterations involving the two genes, we evaluated impact of BAP1 and MTAP status on PD-L1 and TMB. TMB (1.74 mut/mb vs 1.74 mut/mb) and PD-L1 expression (50% vs 54%) were comparable in BAP1-altered vs wildtype specimens. Although TMB was comparable in MTAP-deficient and MTAP-intact tumors (1.25 mut/mb vs 1.74 mut/mb), more tumors with MTAP loss expressed PD-L1 (68% vs 44%, p = 0.0004). Conclusions: Compared to epithelioid MPM, non-epithelioid tumors demonstrate comparable TMB, higher PD-L1 expression, and enrichment for MTAP loss. As MTAP is frequently altered in MPM, further study is indicated to explore the relationship between MTAP status and MPM biology, including sensitivity to therapeutics such as immunotherapy and synthetic lethal approaches.
Safety and efficacy of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer: Update from the ARROW trial.
Authors: Curigliano Giuseppe , Gainor Justin F. , Griesinger Frank , Thomas Michael , Subbiah Vivek , Baik Christina S , Tan Daniel Shao-Weng , Lee Dae Ho , Misch Daniel , Garralda Elena , Kim Dong-Wan , Paz-Ares Luis G. , Mazieres Julien , Liu Stephen V. , Kalemkerian Gregory Peter , Houvras Yariv , Bowles Daniel W. , Mansfield Aaron Scott , Zalutskaya Alena , van der Wekken Anthonie J.
Published: June 2021

9089

Background: RET fusions are targetable oncogenic drivers in 1–2% of non-small cell lung cancer (NSCLC). ARROW (NCT03037385) supported the US FDA approval of pralsetinib, a highly potent oral selective RET inhibitor for RET-altered NSCLC and thyroid cancer. Here, we present updated results for a larger population of patients with RET fusion–positive NSCLC enrolled in ARROW. Methods: ARROW is a phase 1/2 open-label study conducted at 84 sites in 13 countries. Phase 2 expansion cohorts included patients with RET fusion–positive NSCLC. Initially, all treatment-naïve patients were not candidates for platinum-based therapy, a requirement removed by protocol amendment in July 2019. Primary objectives are overall response rate (ORR; blinded independent central review [BICR] per RECIST v1.1), assessed for patients with baseline measurable disease, and safety. Results: Updated analyses were completed as of Nov 6, 2020 (data cut-off), for patients who initiated pralsetinib 400 mg QD by May 22, 2020 (enrollment cut-off). Efficacy results, including analyses for treatment-naïve patients enrolled after eligibility criteria were revised to allow candidates for platinum-based therapy, are shown in the Table. Conclusions: Pralsetinib showed rapid, potent, and durable clinical activity in patients with RET fusion-positive NSCLC (regardless of prior therapies), including poor prognosis patients not eligible for platinum-based therapy. Overall, pralsetinib was well-tolerated. These data highlight the need for RET testing early in the course of disease to identify candidates who may benefit from treatment with pralsetinib. Clinical trial information: NCT03037385. [Table: see text]
Clinicopathologic and genomic correlates of tumor-infiltrating immune cells and immunotherapy efficacy in NSCLC.
Authors: Alessi Joao Victor Machado , Ricciuti Biagio , Nishino Mizuki , Weirather Jason L. , Le Ann-Elisabeth , Lindsay James , Sharma Bijaya , Felt Kristen , Sholl Lynette M. , Rodig Scott J. , Awad Mark M.
Published: June 2021

9121

Background: Tumor-infiltrating immune cells and PD-L1 expression are associated with improved clinical outcomes in patients (pts) with NSCLC treated with immune checkpoint inhibitors (ICIs). However, as tumor-infiltrating immune cells are not a well-established biomarker for NSCLC, further data are needed to integrate and identify clinicopathological and genomic factors that influence the tumor microenvironment. Methods: We collected clinicopathologic and genomic data from pts with NSCLC who underwent multiplexed immunofluorescence. Uniform Manifold Approximation and Projection (UMAP) was used to identify distinct immunophenotypic clusters according to the number of intratumoral PD-1+ immune cells (ICs), CD8+, and Foxp3+ T cells, as well as PD-L1 on tumor and immune cells. An unbiased recursive partitioning (URP) algorithm was used to investigate an optimal cluster with respect to objective response rate (ORR) in the subset of pts treated with ICIs. Results: Among 304 pts, UMAP identified 5 clusters: PD-L1-high with high vs low CD8+ and PD-1+ ICs (clusters A & B, respectively); PD-L1-low with high vs low CD8+ and PD-1+ ICs (clusters C & D respectively); PD-L1-low and moderate levels of CD8+ and PD-1+ ICs (cluster E). Clinicopathological characteristics of the clusters shown in Table. URP analysis identified immune rich clusters A and C as optimal responders to ICIs. From the start of ICIs, we observed a significantly higher ORR (53.3% vs 4.3%; P<0.001), a significantly longer median progression-free survival (mPFS 25.6 vs 3.7 months; HR: 0.12 [95% CI: 0.05-0.32]; P<0.001), and longer median overall survival (mOS 45.1 vs 22.3 months; HR: 0.25 [95% CI: 0.1-0.68]; P=0.006) in clusters A + C (N=15) vs other clusters (N=23). After adjusting for other variables such as performance status, histology, presence of oncogenic driver mutation, and line of treatment, clusters A + C were significantly associated with improved mPFS (HR: 0.08 [95% CI: 0.03-0.24], P<0.001) and mOS (HR: 0.11 [95% CI: 0.03-0.40], P<0.001). Conclusions: Incorporation of multiplex immunofluorescence may improve prediction of response and resistance to immunotherapy in NSCLC.[Table: see text]
Toxicity, response, and survival in older adults with metastatic melanoma treated with checkpoint inhibitors.
Authors: De Glas Nienke A , Bastiaannet Esther , van den Bos Frederiek , Mooijaart Simon , Van Der Veldt Astrid Aplonia Maria , Suijkerbuijk Karijn , Aarts Maureen J.B. , van den Berkmortel Franchette , Blank Christian U. , Boers-Sonderen Marye , van den Eertwegh Alfonsus Johannes Maria , de Groot Jan Willem , Hospers Geke , Haanen John B. A. G. , Piersma Djura , Van Rijn Rozemarijn , Ten Tije A. J. , Wouters Michel W.J.M. , Portielje Johanna Elisabeth A. , Kapiteijn Ellen
Published: June 2021

9544

Background: Checkpoint inhibitors have strongly improved survival of patients with metastatic melanoma. Trials suggest no differences in outcomes between older and younger patients, but only relatively young patients with a good performance status were included in these trials. The aim of this study was to describe treatment patterns and outcomes of older adults with metastatic melanoma, and to identify predictors of outcome. Methods: We included all patients aged ≥65 years with metastatic melanoma between 2013 and 2020 from the Dutch Melanoma Treatment registry (DMTR), in which detailed information on patients, treatments and outcomes is available. We assessed predictors of grade ≥3 toxicity and 6-months response using logistic regression models, and melanoma-specific and overall survival using Cox regression models. Additionally, we described reasons for hospital admissions and treatment discontinuation. Results: A total of 2216 patients were included. Grade ≥3 toxicity did not increase with age, comorbidity or WHO performance status, in patients treated with monotherapy (anti-PD1 or ipilimumab) or combination treatment. However, patients aged ≥75 were admitted more frequently and discontinued treatment due to toxicity more often. Six months-response rates were similar to previous randomized trials (40.3% and 43.6% in patients aged 65-75 and ≥75 respectively for anti-PD1 treatment) and were not affected by age or comorbidity. Melanoma-specific survival was not affected by age or comorbidity, but age, comorbidity and WHO performance status were associated with overall survival in multivariate analyses. Conclusions: Toxicity, response and melanoma-specific survival were not associated with age or comorbidity status. Treatment with immunotherapy should therefore not be omitted solely based on age or comorbidity. However, the impact of grade I-II toxicity in older patients deserves further study as older patients discontinue treatment more frequently and receive less treatment cycles.[Table: see text]
IL-6 blockade for prophylaxis and management of immune-related adverse events (irAEs) with anti-PD-1 based immunotherapy.
Authors: Dimitriou Florentia , Hogan Sabrina A , Cheng Phil F , Dummer Reinhard , Menzies Alexander M. , Long Georgina V.
Published: June 2021

9553

Background: Immune checkpoint inhibitors (ICIs) have activity across many tumor types, but activation of the immune system may also lead to significant, often steroid-refractory irAEs. We sought to determine the activity of tocilizumab, an anti-IL6R monoclonal antibody (mAb), in treatment or prevention of auto-immune irAE in ICI-treated patients (pts). Methods: Institutional databases from 2 melanoma centers were reviewed for pts treated with ICIs and tocilizumab. Treatment and melanoma outcomes were prospectively assessed. Longitudinal assessment of c-reactive protein (CRP) and assessment of clinical improvement (defined as irAE resolution to grade ≤1 CTCAEv5) or prophylaxis (absence of flare, defined as ≥ grade 2) were utilized to evaluate the benefit of tocilizumab. Paired Wilcoxon rank test was used to compare CRP levels prior to ICI administration, at the onset of irAEs and after tocilizumab administration. Results: 22 pts were identified. 2 pts were treated prophylactically (pre-existing dermatomyositis [n = 1] and giant cell arteritis [GCA, n = 1]) before the administration of PD1. 20 pts were treated for management of irAEs due to PD1 +/-CTLA4 (multiple concurrent irAEs [n = 3], steroid refractory irAES [hepatitis & pancreatitis, n = 2], steroid+anti-TNFα refractory colitis [n = 2], steroid+other immunosuppressive-refractory hepatitis [n = 1], cytokine release syndrome-related AEs [n = 6], musculoskeletal irAEs [n = 6]). 15 (68.2%) pts with irAEs required hospitalization and of those, 13 (86.7%) received tocilizumab whilst inpatient. Median time to irAE onset from ICI start was 48 days (range 8-786) and from irAE onset to tocilizumab administration 32 days (range 1-192). Median time to irAE resolution from tocilizumab administration was 7 days (range 1-799). Clinical improvement/benefit was demonstrated in 21/22 patients; one patient with ir-hepatitis did not respond. Median CRP prior to ICI administration was 32mg/L (range 0.3-99), at the onset of irAE 49.5mg/L (range 0.3-251, p = 0.055) and after the tocilizumab administration 18mg/L (range 0.3-18, p = 0.0015). Tocilizumab was well tolerated with self-limiting and transient toxicities in 17 (77.3%) patients. There were two grade 4 events; gastrointestinal tract perforation and Fournier gangrene, the latter unrelated to tocilizumab. Two (9%) patients died due to melanoma. From start of ICI, median progression-free survival (PFS) was 5.88 months and median overall survival (OS) was not reached. Conclusions: Tocilizumab was a well-tolerated and effective steroid-sparing treatment for both management of irAEs, as well as prevention of a flare of pre-existing auto-immune disorders during ICI administration. Prospective trials to evaluate its efficacy and impact on cancer outcomes compared with standard strategies are required.
Outcomes of non-treatment naive melanoma patients with central nervous system relapse.
Authors: Pimentel Muniz Thiago , Lone Hadee , Arteaga Diana Paola , Gray Diana , Silveira Vilbert Pereira Maysa Tamara , Mantle Luke , Singh Raviya , Genta Sofia , Saibil Samuel , Hogg David , Spreafico Anna , Butler Marcus O.
Published: June 2021

9557

Background: Melanoma has a high probability of central nervous system (CNS) spread. Although first line nivolumab and ipilimumab resulted in 56% response rate and 29.2 months median overall survival (OS) in patients with melanoma brain metastases (MBM), there is paucity of data for patients who develop MBM after prior systemic therapy. As this subgroup is often underrepresented in clinical trials, we aimed to evaluate the OS of non-treatment naïve patients who develop MBM and identify factors related to survival. Methods: In this single-center, retrospective study, consecutive melanoma patients with > 90 days from exposure to either immune checkpoint inhibitor (ICI), targeted therapy (TT), or chemotherapy, to CNS relapse were included. OS was defined as the time between CNS relapse and death by any cause. The Log-Rank method was used to calculate OS. Cox regression analysis was used to identify differences between subgroups. Variables with a p value < 0.1 were included in a multivariate model. A p value < 0.05 was considered statistically significant. Results: Between 2012 and 2018, 135 patients were identified. Median age was 57 (29-92) years, 92 (68%) were male, and median number of prior systemic therapies was 2 (1-6). One-hundred and nine (81%) patients had cutaneous melanoma; acral lentiginous melanoma (ALM) comprised 11 (8%) patients. Molecular studies were available for 123 patients, of whom 61 (50%) were BRAF V600 mutant. Eighty-nine (66%) patients had prior ICI, of whom 33 (37%) had prior exposure to both anti-PD1 and anti-CTLA-4, either as monotherapy or combination. Amongst the BRAF V600 mutant population, 48 (79%) had prior TT. Radiotherapy was given to 112 patients, of whom 55 (49%) had SRS. Median follow-up was 41 (95% CI 30-51) months. Median OS was 6.4 (95% CI 5.3-7.5) months. Patients with ALM, > 3 MBM, ECOG 2-4 and active treatment at CNS relapse (< 30 days from last dose of treatment to MBM diagnosis) were at increased risk of death, whilst subsequent treatment with ICI was related to better survival (Table). On multivariate analyses, age ( p = 0.007), subtype ( p = 0.04), number of MBM ( p = 0.01), active treatment at CNS relapse ( p < 0.001) and subsequent ICI ( p = 0.002) remained statistically significant. Exploratory analyses suggested subsequent treatment with anti-PD1 + anti-CTLA-4 (n = 42) compared favourably to subsequent anti-CTLA-4 only (n = 21) (13 x 7 months, p = 0.004), and was independent of prior ICI. Conclusions: Previously treated melanoma patients who develop MBM have a poor prognosis, but subsequent ICI therapy seems to be associated with better OS. Further clinical investigation to identify optimal anti-PD1-based therapies is warranted for non-treatment naïve patients who develop MBM.[Table: see text]
Association between estrogen receptor status and Oncotype Dx breast recurrence score.
Authors: Khan Noman Ahmed Jang , Abdallah Mahmoud , Gress Todd W. , Alsharedi Mohamed Farouq
Published: June 2021

e12519

Background: The 21 gene assay Oncotype Dx Breast Recurrence Score (RS) is currently the standard of care to determine if adjuvant chemotherapy is needed in early stage node negative, hormone receptor positive, HER-2 negative breast cancer. In current American society of clinical oncology (ASCO) guidelines there is little or no benefit of adjuvant chemotherapy in patients older than 50 years whose tumors have Oncotype DX RS <26, and for patients 50 years or less whose tumors have Oncotype DX RS <16. We sought to evaluate the percentage of estrogen receptor (ER) expression as a surrogate measure of determining adjuvant chemotherapy by examining the relationship between ER expression and RS. Methods: We identified 301 patients from years 2015 to 2019 from our cancer registry with early stage hormone receptor positive breast cancer and had oncotype DX testing performed. We divided patients into three groups: Group 1 (ERG1) with ER <10%; Group 2 (ERG2) with ER 10-49%; and Group 3 (ERG3) with ER equal or >50%. We also collected information on tumor size (cm), tumor grade, Nottingham score, and ki-67 percentage. A sub-group analysis was performed for patients < 50 years age (n=30). We compared all continuous variables across ER groups using the Kruskal-Wallis rank test and individual between group comparisons using the Wilcoxon rank sum test. All statistical tests performed utilized a two-tailed p value of <0.05 with the Bonferroni correction for multiple comparisons. Results: Among 301 patients with early stage hormone receptor positive breast cancer, 89.1% were ductal, 7.9% lobular, and 2.9% mixed histology. Median age was 68, 58 and 66 for ERG1, ERG2, and ERG3, respectively (p = 0.41). Median RS was 36 (ERG1), 23 (ERG2), and 16 (ERG3) (p = 0.78 for ERG1 vs. ERG2; p = 0.01 for ERG1 vs. ERG3). As expected, tumor grade, tumor size, and Nottingham score decreased significantly from ERG1 to ERG3. For patients <50 years, median age was 44, 46 and 45 for ERG1, ERG2, and ERG3, respectively (p = 0.75). Median RS was 10 (ERG1), 24 (ERG2) and 18 (ERG3) (p = 0.04 for ERG1 vs. ERG2; p = 0.17 for ERG1 vs. ERG3). Conclusions: We found a significant association between estrogen receptor levels and Oncotype Dx recurrence score (RS) in patients with early stage hormone receptor positive breast cancer patients. Further studies are needed to determine the predictive ability of hormone receptor levels on the outcomes of patients treated for early stage hormone receptor positive breast cancer.