bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating costs of adverse events (AEs) and healthcare resource use (HRU) in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) receiving tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel): A summary of real-world evidence.
Authors: Yang Hongbo , Qi Cynthia Zhengyun , Dalal Anand , Bollu Vamsi , Zhang Jie , Zhang Su , Lim Stephen
Published: June 2021

e19551

Background: The AE rates and HRU reported in multiple real-world evidence (RWE) studies of chimeric antigen receptor T-cell (CAR-T) therapies tisa-cel and axi-cel in r/r DLBCL have differed from those in their clinical trials. However, the cost implications from these findings are not well understood in existing literature. This study summarizes information from these RWE studies of tisa-cel and axi-cel and quantifies the associated costs. Methods: A literature review was conducted to identify RWE studies reporting AE rates and HRU of tisa-cel and axi-cel in the United States (US). AE rates and HRU were summarized and the associated costs were estimated using a micro-costing approach. Costs of AE management included hospitalization and pharmacy costs, such as intensive care unit (ICU) stays, inpatient admissions, and medications for the treatment of cytokine release syndrome (CRS) and neurotoxicity events (NE). HRU costs included hospitalization, ICU stays, and outpatient visit costs. Unit costs were from public health databases that are representative of US healthcare system and from literature. Costs were inflated to 2020 US dollars. A range was reported to present evidence if inputs are available from multiple studies. Results were summarized for tisa-cel and axi-cel separately. Results: Four publications were identified: Jaglowski 2019, Pasquini 2019, Riedell 2019, and Jacobson 2020. Across studies, grade 3+ CRS and NE occurred in 1%-4% and 0%-5% of tisa-cel-treated patients and 7%-16% and 20%-35% of axi-cel-treated patients, respectively. Tocilizumab usage was reported in 14%-20% of tisa-cel- and 62%-71% of axi-cel-treated patients. CAR-T infusion was inpatient for 36% of tisa-cel- and 92%-100% of axi-cel-treated patients. The median hospitalization days was 2 for tisa-cel and 15-16 for axi-cel. ICU transfer was observed for 7% and 28%-38% of tisa-cel- and axi-cel-treated patients, respectively, with median stays of 4 and 5 days, respectively. The median number of outpatient visits within 28 days after infusion was 6 for tisa-cel and 4 for axi-cel. The total estimated costs for managing AEs per patient were $843-$1,962 for tisa-cel and $5,979-$10,878 for axi-cel. The total estimated HRU costs per patient were $3,321 for tisa-cel and $32,394-33,166 for axi-cel. Conclusions: RWE studies suggest that patients with r/r DLBCL receiving tisa-cel had numerically lower AE rates, HRU, and cost burden than those receiving axi-cel in the US. The additional cost burden for axi-cel was primarily driven by the incremental ICU and hospitalization care due to a higher proportion of inpatient infusion among patients receiving axi-cel. Further research is warranted to compare the costs associated with the two CAR-Ts in r/r DLBCL.
Effectiveness of intravenous high-dose methotrexate for prevention of relapse in patients with DLBCL.
Authors: Alotaibi Hind , Motabi Ibraheem , Butt Ahmad , AlShehry Nawal , Marei Mohammed , Tailor Imran , Altaf Sayed , Zaidi Syed , Alnoamani Mohammed , Alrajhi Abdullah , Albtoosh Bilal , Alzahrani Kamal , Alfayez Mansour
Published: June 2021

e19562

Background: Central nervous system (CNS) relapse develops in 2-10% of patients with diffuse large B cell lymphoma (DLBCL) and has an adverse prognosis. Tools like IPI and CNS-IPI scores identify patients at high risk of systemic or CNS relapse based on the presence of established risk factors ( Schmitz et al. JCO 2016). International guidelines propose prophylactic intravenous high-dose methotrexate (HD-MTX) for patients at high risk of CNS relapse; however, limited data is backing this approach. Methods: We conducted a retrospective review of newly diagnosed DLBCL patients aged 18-75 years treated with curative intent at large academic medical centers in Riyadh, Saudi Arabia, between 2015-2018. Patients who were planned for CNS HD-MTX after cycles 2, 4, and 6 of R-CHOP and received at least one HD-MTX cycle were included. Results: We identified 35 DLBCL patients who received at least one R-CHOP cycle with one cycle of HD-MTX. The median IPI and CNS-IPI score were 3, (range = 0-4) and 3, (range = 0-5), respectively. The median number of R-CHOP cycles received was 6 (range 3-6) and HD-MTX 3 (range 1-6). The overall response rate was 91%, with 3 (9%) primary refractory patients per interim evaluation on cycle 3 of R-CHOP. Achieving complete remission after six cycles of RCHOP was noted in 80%, with four additional patients showed residual disease at the end of treatment evaluation. The entire cohort's overall survival was not reached, and five years estimated survival is 75%. With a median follow-up duration of 37.3 months, none of the patients relapsed after achieving CR at the end of treatment evaluation. The risk of systemic or CNS relapse in our cohort was 0%. In restricting the analysis to CNS-IPI of ≥ 4, a total of 13 patients with a median follow-up of 42 months were included; four patients did not achieve CR by the end of treatment, while nine patients continue to be in CR without any evidence of relapsed disease. Conclusions: High-dose methotrexate with high-intensity chemoimmunotherapy (R-CHOP) seems to be associated with an improvement in the expected rate of CNS relapse. Our data set is small, and a more extensive study evaluating HD-MTX's effectiveness in high-risk DLBCL is warranted.[Table: see text]
Chemotherapy-based stem cell mobilization in multiple myeloma patients treated with novel agents: The Mayo Clinic experience.
Authors: Vaxman Iuliana , Muchtar Eli , Kapoor Prashant , Kumar Shaji , Dispenzieri Angela , Buadi Francis , Dingli David , Gonsalves Wilson I. , Kourelis Taxiarchis , Warsame Rahma M. , Lacy Martha , Hogan William J. , Gertz Morie A.
Published: June 2021

e20000

Background: In the novel agents’ era, refractoriness to induction in Multiple Myeloma (MM) is relatively rare. This population remain an unmet need and are often excluded from clinical trials. In the current era, chemotherapy-induced stem cell collections are used at Mayo Clinic in “poor responders” to induction, such as patients that progress prior to ASCT or patients with significant disease burden after induction. Methods: This is a retrospective study that includes all MM patients the underwent chemo-mobilization between January 2012 and September 2020 at Mayo Clinic. We compared our cohort to a cohort of 125 matched patients that were transplanted over the same time period and underwent mobilization with G-CSF and “on-demand” plerixafor. We matched the cohorts by level of response by IMWG at pre-transplant evaluation. Results: 125 newly diagnosed MM patients who received novel agents’ induction and had a poor response to induction were mobilized using IV intermediate-dose cyclophosphamide (83%) or VDT-PACE (17%) plus G-CSF and “on-demand” plerixafor. The median PFS and OS of the chemo-mobilized cohort were 16 months (95% CI 11-20) and 47 months (95% CI 37-71), respectively. Patients receiving chemo-mobilization had higher stem cell yields than the growth factor only cohort (median 9.88X106 cells/kg versus median 8.77X106 cells/kg, respectively (P<0.001)). The safety profile of chemo-mobilization was favorable, with no difference between the two groups in length of hospitalization during ASCT (P=0.95), days to neutrophil or platelet engraftment, and risk of bacteremia (P=0.38). 29% of the chemo-mobilized cohort and 66% of the matched cohort required plerixafor for adequate mobilization (P<0.001). Conclusions: Chemo-mobilization enhances stem cell collection in MM patients with a suboptimal response to induction and reduces the need for plerixafor without adversely impacting the post-transplant clinical course. [Table: see text]
Outcomes of patients with multiple myeloma treated at a regional Australian center compared to a metropolitan Australian center.
Authors: Ai Sylvia , Kang Sharlyn , Presgrave Peter , Cartwright Kim , Warburton Pauline , Desai Shrinivas , Parmar Gurdeep
Published: June 2021

e20003

Background: A number of studies have demonstrated poorer outcomes for patients with cancer who live in rural/regional areas compared to metropolitan areas. There is conflicting information on the effect of rurality on outcomes of patients with multiple myeloma, and limited information regarding the cause of this discrepancy. Methods: Retrospective analysis of demographic, treatment and outcomes of 238 patients newly diagnosed with multiple myeloma between 2002-2019 in the Illawara Shoalhaven Local Health District. Results: Patients being treated in a regional cancer care centre had lower overall survival compared to those treated at a metropolitan cancer care centre (median OS = 63.6 months vs. 43.8 months, p=0.004), and a trend towards lower progression-free survival (median PFS = 24.7 months vs. 19.8 months, p=0.228) despite treatment by the same group of hematologists. There was a lower rate of autologous transplantation for patients treated at a regional cancer care centre compared to a metropolitan cancer care centre (36% vs. 18%, p=0.007). Conclusions: Survival differences between patients with multiple myeloma living in regional areas compared to metropolitan areas may be due to lower rates of autologous transplantation.
Tandem versus single autologous stem cell transplant: A patient-reported outcome.
Authors: Molina Thomas H. , Sweeney Nathan W. , Cole Nolan , Ahlstrom Jenny
Published: June 2021

e20026

Background: Whether tandem autologous stem cell transplant (ASCT) is superior to single ASCT for new diagnosed multiple myeloma (MM) patients remains a subject of discussion in the era of novel agents. This project analyzed patient-reported outcomes to single ASCT and tandem ASCT utilizing an online patient-centered platform. Methods: We analyzed patient-reported treatment outcomes pertaining to tandem ASCT and single ASCT from HealthTree Cure Hub ( www.healthtree.org ). In this study, we examined whether patients reported a reduction or no reduction in their myeloma after their tandem or single ASCT. The association between stem cell transplant and myeloma outcome was compared by chi-squared test. Results: In this retrospective analysis of 945 MM patients, we compared two groups, those that reported receiving a tandem ASCT (n = 75) and those that reported receiving a single ASCT (n = 870). Our analysis revealed an association between patients who reported receiving a tandem ASCT and a reduction of their myeloma (chi-square (1) = 3.87, p = .04), compared to patients who reported receiving a single ASCT. Conclusions: Tandem ASCT was perceived by patients to be superior over single ASCT in regard to myeloma reduction for the HealthTree patient population. A more in-depth analysis of the patient-provided health data from HealthTree could aid in determining factors related to survival as well as help to quickly answer lingering questions related to tandem ASCT, such as timing, genetic factors, progression free survival, and more.[Table: see text]
Characterization of smoldering multiple myeloma: A population-based cohort study.
Authors: Fatoki Raleigh Ayoolu , Khan Adnan Ahmed , Carpenter Diane M. , Baer David M.
Published: June 2021

e20028

Background: There is increasing interest in characterizing Smoldering Multiple Myeloma (SMM) due to the availability of novel therapies shown to delay symptomatic progression to Multiple Myeloma (MM) with considerably less toxicity. The lack of population-based disease registries has made epidemiologic data on SMM difficult to acquire. Existing cohort studies of SMM patients have largely been conducted in specialized referral centers. This surveillance study characterizes the epidemiology of SMM in a real-world, clinical population using data from a large, integrated healthcare delivery system. Methods: We performed a retrospective study of all new SMM cases identified in Kaiser Permanente Northern California (KPNC) during 2010-2017, based on either (or (2) a new MM diagnosis in the KPNC Cancer Registry without initiation of plasma cell-directed therapy within 1 year of diagnosis. Those without KPNC membership for at least 1 year after diagnosis were excluded. Age at diagnosis, sex, race/ethnicity, and Charlson Comorbidity Index (CCI) at diagnosis were examined. The incidence of SMM was calculated using KPNC membership denominators, and a 2-sided Cochran-Armitage test was used to test for trend. Among the SMM cohort, characteristics were examined using the chi-squared test, including data before/after the Nov 2014 International Myeloma Working Group (IMWG) diagnostic criteria update. Results: A total of 251 new SMM cases were identified from 2010-2017. The average annual incidence of SMM was 1.2 per 100,000, increasing from 1.0 per 100,000 in 2010 to 1.5 per 100,000 in 2017 (p<0.05 for trend). The demographic characteristics of the SMM cohort were notable for mean age 70.0 ± 11.7 years, 63.8% male, and 61.0% non-Hispanic White, 17.1% Black, 10.0% Hispanic, and 11.6% Asian. Overall, 73.7% had at least 1 comorbidity, based on CCI. When comparing 116 SMM cases diagnosed after the IMWG update to 135 cases diagnosed before the IMWG update, those diagnosed after the revised IMWG guidelines were significantly more likely to have at least 1 existing comorbidity (80.2% vs 68.2%, p=0.03). Conclusion We identified a contemporary cohort of patients with SMM from a large, integrated healthcare system. During our 8-year study period, the annual incidence of SMM increased slightly, including after 2014 when the IMWG criteria for SMM were refined. We observed that patients diagnosed after the 2014 IMWG update were more likely to have at least 1 comorbidity. Whether these trends relate to background population characteristics or are specific to recognized SMM cases bears further study. Follow-up analyses will examine the rate of progression from SMM to MM and the presence or absence of severe, irreversible, end-organ damage at the time of progression.
Association of kappa light chain restriction with peripheral neuropathy among patients with non-IgM monoclonal gammopathy of undetermined significance.
Authors: Dasanu Constantin A. , Kaur Jaspreet , Tuler Shahaf , Farrell Stephanie , Plaxe Steven C.
Published: June 2021

e20040

Background: Monoclonal gammopathy of undetermined significance (MGUS) can be associated with significant neurologic morbidity. Of non-IgM MGUS, types IgG and IgA are most commonly associated with peripheral neuropathy (PN). Methods: With IRB approval, we conducted a retrospective cohort study of consecutive patients with non-IgM type MGUS treated at our institution from 2014-2021. Other conditions potentially causing PN were excluded. Statistical analysis: Descriptive statistics were calculated to characterize the study population, and Relative Risk (RR) of PN was evaluated for selected patient, and disease, related factors. P < 0.05 was defined as statistically significant. Results: During the study period, 94 patients with non-IgM type MGUS were seen and comprised the study population. Twenty-two (23.4%) had evidence of PN. Median age was 74; 82% (18/22 ) were Caucasian; 73% (16/22) were women. 82% (18/22) patients had MGUS type IgG kappa or IgA kappa. We identified only 2 patients with each MGUS kappa light chain (LC) and MGUS IgG lambda. Median M-protein size was 0.11 g/dL, and median free LC value was 6.84 mg/L. Incidence/severity of kidney disease was similar in non-IgM MGUS patients with and without PN (p > 0.05). RR of PN was not found to be significantly different based on race or gender, although there appeared to be a tendency for women to be at higher risk compared to men (RR = 1.98, 95% CI = 0.85 to 4.60, p = 0.114.) Kappa LC restriction was strongly associated with PN (RR = 4.31, 95% CI = 1.58 to 11.78; p = 0.004). Electromyographic (EMG) studies identified 14 patients (64%) with distal symmetric axonal neuropathy (DSAN) and 8 patients (36%) with chronic inflammatory demyelinating polyneuropathy (CIDP). Clinically severe PN was identified in 11 (50%) patients; all were subsequently treated with IVIg therapy. Only 5/11 (45%) patients responded to IVIg, and the responses were only partial and transient. Conclusions: This is the first report, to our knowledge, of a significant association of kappa (as opposed to lambda) LC restriction with PN among patients with non-IgM type MGUS. Further investigation is warranted to explain this finding, elucidate pathophysiology and aid in developing more effective therapeutic options. Pending mechanistic characterization of this association, trials of contemporary agents used to treat other plasma cell disorders may be in order. Final statistical analysis, comparison to published series and significance will be presented.
Real-world prognostic model for malignant pleural mesothelioma.
Authors: Nasser Abdullah , Baird Andrew , Saint-Pierre Mathieu D. , Laurie Scott A. , Wheatley-Price Paul
Published: June 2021

e20562

Background: Two mesothelioma prognostic models have been suggested: European Organisation for Research and Treatment of Cancer (EORTC) and Cancer and Leukaemia Group B (CALGB) models. Both were based on clinical trial patients enrolled in the mid-1980s to early-1990s. Several changes to mesothelioma management have been adopted since publication of these models, including improved surgical and palliative interventions and changes to systemic therapy. Methods: With ethics approval, we collected and analyzed the health data of malignant pleural mesothelioma (MPM) patients with histologically confirmed diagnosis treated at our institution between January 1991 and March 2019. The primary endpoint was overall survival (OS). Univariate analysis was used to identify significant predictors of survival, which were then used to construct a multivariate survival tree with complete case-analysis and bootstrapping. Patients were then stratified into three prognostic groups based on their median OS. Results: 337 patients were included in the study; 309 (91.7%) were dead at last follow-up. The median OS was 9.4 (8.1-11.5) months for the entire population. Eastern Cooperative Oncology Group (ECOG) performance status (PS), histology, white blood count, platelets, International Mesothelioma Interest Group stage, age and hemoglobin were independent predictors of survival. The final pruned survival tree was based on 285 patients and incorporated the first five predictors. Good, intermediate and poor prognostic groups had median OS of > 12 months, 6-12 months, and < 6 months, respectively. Factors associated with the prognostic groups were: good prognosis: ECOG 0-1, normal platelets, stage 1, 2 and epithelioid histology; intermediate prognosis: ECOG 0-1 with either stage 3, 4 and/or sarcomatoid or biphasic histology; poor prognosis: ECOG 2-4 regardless of other factors. Conclusions: In contrast to EORTC/CALGB, real world evidence generates these prognostic groups with face validity but will need independent validation. Our data does not account for recent advances including immunotherapy, and thus patients with non-epithelioid histology may have better survival than predicted.[Table: see text]
Effects of trilaciclib prior to chemotherapy ± atezolizumab on T-cell activation in patients with newly diagnosed extensive-stage small cell lung cancer.
Authors: Stevens Aaron D. , Daniel Davey B. , Goldschmidt Jerome H. , Fields Paul A. , Banbury Barb , Wolfe Steven , Glass Jarrett , Horton Janet K. , Sorrentino Jessica
Published: June 2021

e20582

Background: Chemotherapy ± immunotherapy has demonstrated meaningful clinical benefit to patients (pts) with extensive-stage small cell lung cancer (ES-SCLC); however, chemotherapy-induced damage to the immune system can potentially diminish treatment efficacy. Trilaciclib (T) is an intravenous cyclin-dependent kinase 4/6 inhibitor that protects hematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection) and may directly enhance antitumor immunity. Here, we evaluated the immune effects of T in pts with ES-SCLC receiving T or placebo (P) prior to first-line etoposide plus carboplatin (E/C) or E/C plus atezolizumab (E/C/A) in two phase 2 clinical trials. Methods: Genomic DNA, extracted from peripheral blood mononuclear cells (baseline and on treatment) and archival tumor tissue (baseline), was analyzed using the immunoSEQ® Assay (Adaptive Biotechnologies). T-cell receptor (TCR) β CDR3 regions were amplified and sequenced to identify and quantitate the abundance of each unique TCRβ CDR3. Clonal frequencies were compared at baseline and on treatment, and statistical differences between T and P were determined by Wilcoxon rank sum test. Antitumor response was defined as complete/partial response. Results: In both studies, peripheral T-cell clonal expansion was greater among pts receiving T versus P. Among pts receiving E/C, those in the T/E/C group with an antitumor response had significantly more peripheral clonal expansion than P responders (median 23 vs 12 clones; P= 0.04) and a greater number of tumor-associated expanded clones ( P= 0.03). T responders had more newly detected expanded peripheral clones compared with P responders (6 vs 1.5 clones; P= 0.06) and T nonresponders ( P= 0.02). Increased clonal expansion in T responders was more evident after two cycles of E/C versus four, suggesting that T results in a rapid T-cell response. Similarly, among pts receiving E/C/A, those in the T/E/C/A group with an antitumor response had significantly more peripheral clonal expansion than P responders (median 90 vs 43 clones; P= 0.002) and T nonresponders ( P= 0.016). T responders also had more newly expanded peripheral clones compared with P responders (68 vs 11 clones; P= 0.003) and T nonresponders ( P= 0.02). There was no increase in tumor-associated expanded clones among T responders compared to P responders, possibly due to the time point at which clonal expansion was assessed (after four cycles) or the addition of atezolizumab. Associations between peripheral and tumor-associated clonal expansion and survival will be presented. Conclusions: The data suggest that, among pts treated with T/E/C or T/E/C/A, increased clonal expansion is associated with clinical response, indicating that T may enhance antitumor immunity in pts with ES-SCLC treated with chemotherapy.
Assessment of National Comprehensive Cancer Network (NCCN) guideline adherence for lung cancer in a community teaching hospital during COVID-19 pandemic.
Authors: Paravathaneni Mahati , Thota Vihitha , Baralo Bohdan , Mulla Sana , Choi Eugene Jinkyu , Thirumaran Rajesh
Published: June 2021

e20589

Background: Coronavirus disease 2019 (COVID-19) evolved into a worldwide pandemic leading to devastating complications. In healthcare, significant changes were made to reallocate resources to cater to an increasing number of hospital admissions and prevent infection spread. Reallocation of the health care staff led to the scarcity of care in outpatient facilities, including infusion centers, until the widespread adoption of Telehealth. Treating lung cancer patients with immunochemotherapy and radiotherapy has been incredibly challenging due to the pandemic, especially in regard to balancing malignancy treatment with limiting exposure of vulnerable patients to acute life-threatening infection. In addition, being unable to provide appropriate treatment to cancer patients can result in decreased functional capacity, loss of treatment window, and increased mortality. A multidisciplinary approach can prevent these outcomes by anticipating challenges early and streamlining resources appropriately to provide better patient care. In this study, we aimed to assess the adherence of NCCN guidelines for lung cancer at a community hospital in Philadelphia during the pandemic. Methods: A retrospective chart review was performed of patients diagnosed and receiving active treatment for primary lung cancer between March 1, 2020, and December 31, 2020, at Mercy Catholic Medical Center. Fifty cases of primary lung cancer undergoing active treatment were identified. Type and staging of lung cancer, NCCN guidelines’ adherence, COVID-19 exposure, and missed treatments were reviewed and analyzed. Results: Of the 50 cases reviewed, 92% had non-small cell lung cancer (NSCLC), and 8% had small cell lung cancer (SCLC). Among NSCLC, 72% had adenocarcinoma, 12% had squamous cell carcinoma, and 8% had large cell carcinoma. Stage IV lung cancer consisted of 46%, followed by 34% of stage I, 14% of stage III, and 6% of stage II. NCCN guideline-directed treatment was initiated in 88% (44/50) of the total patients, with the remaining 12% of the patients either refusing treatment (8%) or were lost to follow-up (4%). COVID-19 infection was diagnosed in 35% of the patients, of which 60% missed less than two chemotherapy sessions and 40% of COVID-19 positive patients who required hospitalization missed more than two cycles. 28% of patients missed treatment sessions due to other factors. This resulted in 61% (27/44) of patients having a disruption in NCCN guideline-directed treatment at some point during the pandemic. Conclusions: Our study results reflect upon the need for developing effective strategies in managing cancer patients. When possible, switching to oral regimens, redefining regimen administration intervals, postponing invasive investigations for asymptomatic patients, and utilizing telemedicine as appropriate should be considered.
Identification of RET fusion as mechanisms of resistance to EGFR tyrosine-kinase inhibitors.
Authors: Bing Zhongxing , Wang Weiran , Wang Danhua , Ma Tonghui
Published: June 2021

e21074

Background: Responses to EGFR-targeted therapy are generally temporary, due to inevitable drug resistance. Although RET fusions have been identified in resistant EGFR-mutant non–small cell lung cancer (NSCLC), their characteristics acquired resistance to EGFR tyrosine-kinase inhibitors (TKIs) are rarely investigated. Methods: We retrospectively reviewed next-generation sequencing data of EGFR+ lung cancer patients, and 8 patients were identified coexisting of EGFR mutations and RET fusion. Their treatment history was collected. Results: The co-occurrence of RET fusion with EGFR oncogenic variations was observed in eight patients, and all of the 8 patients have received previous EGFR-TKI treatment. EGFR mutations were including 4 L858R mutations, 4 exon 19 deletions, and 6 T790M mutations. And the partner genes of RET identified by NGS were including TRIM33 (2/8), GPRC6A (1/8), TLN1 (1/8), KIAA1598 (1/8), SPECC1 (1/8), TRIM24 (1/8) and CCDC6 (1/8). The allelic fractions (AFs) of first-generation EGFR-TKI sensitizing mutations were higher than AFs of EGFR T790M mutations as well as AFs of RET fusion. These RET fusions are fused with rare partner genes, rather than the most common KIF5B in lung cancer. Conclusions: This study extended the knowledge of RET fusion as resistance mechanism to EGFR TKIs in lung cancer. The detection of RET fusions may uncover potential resistance mechanisms of EGFR TKIs, which might inform therapeutic strategies, such as combination-therapy approaches.[Table: see text]
Comprehensive T-cell receptor repertoire of Chinese lung cancer patients related with age.
Authors: Yang Huaxia , Li Xiaoguang , Liu Xinyu , Wang Yadong , Xue Jianchao , Jia Ziqi , Yang Xiaoying , Xu Huihui , Bing Zhongxing , Guo Chao , Tian Zhenyu , Gao Chao , Gu Dejian , Chen Rongrong , Xia Xuefeng , Li Shanqing , Liang Naixin
Published: June 2021

e21076

Background: Cancer is most commonly diagnosed disease worldwide and also a leading cause of death. Cancer is more common in older people, but it can also be found in younger people. As the importance of T cell receptor (TCR) repertoire gains appreciation, particularly given their potential utility for cancer immunotherapeutic prognostication, the characteristics of TCR repertoire are needed. We detected the complementarity determining region 3 (CDR3) by TCR sequence to describe the correlation between diversity and clonality in human’s immune system and age. Methods: The TCRβ repertoire of 47 stage Ia lung cancer patients were analyzed. Genomic DNA was extracted from peripheral blood or tissue, and used to amplified and sequenced the CDR3 region of rearranged TCRβ genes. Finally, we got the relative frequencies of patients T cell clones. Shannon index was calculated on the clonal abundance of all productive TCR sequences. Simpson index also was calculated to measure the clonality of TCR repertoire. MOI was a measure of the similarity in the T cell repertoire between tissue and blood taking into account the specific rearrangements and their respective frequencies. Results: In tissue, the Simpson index ranged from 0.00075 to 0.11466 (mean = 0.01343); Shannon index ranged from 2.91 to 8.95 (mean = 6.26). The age ranged from 27 to 78 (median = 63). Patients were divided into two groups based on median age. The older showed higher Shannon index (p = 0.005) but lower Simpson index (p = 0.0072) than younger patients in tissue. Further, the higher Shannon index was found in younger group in blood(p = 0.0411). Interestingly, the MOI of the older group was significantly higher than that of the younger group (p = 0.0181), suggesting that the older group had a relatively better TME immune response. Then, the usage of V and J gene segments were analyzed. Through statistical analysis and the frequencies of V and J gene usage, we identified that more V and J gene usage were different in older and younger patients. The TRBJ1-1 and TRBJ1-2 were more common in younger patients and TRBJ2-1 and TRBJ2-2 were more common in older patients. There was also more V gene usage different in both groups. Conclusions: Given that the use of certain TRBV regions is predominant in tumor tissues, our results suggested that there may be differences in immune responses of TME to tumors in younger and older patients.
Comparing active immunotherapy efficacy of PD-L1 ≥ 50% NSCLC patients: A systematic review and meta-analysis.
Authors: Hu Yi , Zhao Xiaochen , Bai Yuezong , Cui Longgang , Zhang Fan
Published: June 2021

e21139

Background: Several therapies based on immune checkpoint inhibitors (ICIs) have been approved as the 1L standard of care for PD-L1≥ 50% advanced non-small cell lung cancer (NSCLC). However, little is known about the difference in efficacy between different strategies. We conducted a systematic review and meta-analysis to help clinicians choose more reasonable treatment options. Methods: We searched PubMed, Cochrane library, Embase and major conference proceedings from January 2010 to December 2020 for randomized controlled trials that had available subgroup hazard ratios (HRs) for overall survival according to PD-L1≥ 50%. Only drugs met primary outcome or approved by FDA were included for analysis. The primary outcome was the difference in overall survival (OS). HRs and 95% CI were calculated for the pooled OS using a random-effects model. p<0.05 was considered as statistical difference. Results: A total of 10 randomized controlled trials were included for this meta-analysis. The pooled HR and 95% CI for monotherapy, ICI plus chemotherapy and ICI plus ICI were 0.64 (0.55, 0.74), 0.64 (0.51, 0.79) and 0.70 (0.55, 0.90), respectively. There was no statistical differences between ICI monotherapy and ICI plus chemotherapy (HR 1.00, 95% CI 0.77- 1.30), between ICI monotherapy and ICI plus ICI (HR 0.91, 95% CI 0.69- 1.22) or between ICI plus chemotherapy and ICI plus ICI (HR 0.91, 95% CI 0.66- 1.27). Conclusions: For PD-L1≥ 50% NSCLC patients, active ICI monotherapies showed no different efficacy when compared with ICI combination therapies.
Primary and secondary resistance mechanisms in first, second and third generation tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer patients.
Authors: Suryavanshi Moushumi , Mattoo Sakshi , Sharma Sanjeev Kumar , Mehta Anurag , Batra Ullas
Published: June 2021

e21142

Background: Different molecular mechanisms of on target and off target primary and secondary resistance have been observed in EGFR mutant NSCLC patients after first(1st), second(2nd) and third (3rd) generation of tyrosine kinase inhibitors(TKIs). Next generation sequencing(NGS) offers a comprehensive method of detecting these mechanisms to decide next line of treatment. Methods: We retrospectively analyzed 430 samples of NSCLC for primary and secondary resistance to 1st, 2nd and 3rd TKIs. NGS was performed using thermofischer Ion Torrent Oncomine Focus 52 gene Assay. These cases were divided into 4 groups.1)Primary resistance to first and second generation TKIs 2)Primary resistance to 3rd generation TKI 3)Secondary resistance to 1st and 2nd generation TKI 4) Secondary resistance to 3rd generation TKI.Last group was further subgrouped into A when 3rd generation TKI was offered as second line after 1st or 2nd generation TKIs on detection of T790M and subgroup B when it was given as first line. Results: Group1 had 13 cases. There were 2 cases of complex EGFR exon 19 mutation p.Glu746_Leu747delinsValPro, 4 cases of EGFR exon 20 insertion, 1 case of dual EGFR L833V & H835L mutation, 2 cases with EGFR amplification with EGFR exon 19 del and PIK3CA C420_P421del along with EGFR exon 19 del. Four cases had no additional abnormality. Group 2 had 5 cases:1 case had L858R and E709A dual mutation, 2 cases had KRAS G13C and KRAS G12V along with EGFR exon 19 del. One case had EGFR amplification and one case had MET amplification along with EGFR exon 19 del respectively.Group 3 had 34 cases including 10 cases of EGFR L858R and 24 cases of exon 19 deletion.T790M mutation was detected in 8 patients, MET amplification in 7 cases,one case had both T790M and MET amplification. One case lost the primary EGFR exon 19 del. Others mutations detected were KRAS G13C, PIK3CA H1047R, TP53 R213Q and TP53 C242fs. Group3 had 15 cases with 7 cases in subgroup A and 9 cases in subgroup B. In subgroup A T790M mutation was lost in 6 out of 7 cases.One case which lost T790M developed ALK translocation.One case of EGFR exon 19 del retained EGFR T790M with EGFR C797S in cis allele. Other mutations detected were PIK3CA E542K and KRAS G12C. In subgroup B one case showed EGFR C797S(both cis and trans) besides the primary EGFR exon 19 del. One case showed BRAF G469A along with EGFR exon 19 del. Other mutations detected were CTNNB1 D32N, KRAS G12V, and PIK3CA E542K. Conclusions: Primary and secondary acquired resistance is unavoidable in EGFR mutant advanced NSCLC on any generation of TKIs. NGS offers an advantage in diagnosing mechanism of resistance for further choice of therapy.
Interprofessional care team practices and perspectives on immuno-oncology (IO) therapies for metastatic non-small cell lung cancer (mNSCLC): Insights from a nationwide survey.
Authors: Farris Breanne Y. , Jacobson Anne , Carter Jeffrey D. , Heggen Cherilyn , Socinski Mark A.
Published: June 2021

e21147

Background: Appropriate molecular testing, biomarker-directed treatment selection, and management of immune-related adverse events (irAEs) are essential best practices for managing patients with mNSCLC who are eligible for IO therapies. Identifying real-world challenges among mNSCLC care teams is necessary to inform educational interventions that support optimal care. Methods: From 10/2020 to 01/2021, 75 health care professionals (HCPs) who treat mNSCLC completed surveys assessing practice patterns, challenges, and confidence related to the use of IO therapies. To reflect current real-world practice across treatment settings, surveys were administered at 10 clinics nationwide and through a large oncology practice network. Results: Participants represented the interprofessional mNSCLC care team: oncologists (50%), primary care physicians (23%), advanced practice professionals (13%), and nurses (13%). Nearly one-third reported that PD-L1+ mNSCLC presented greater management challenges than other mNSCLC sub-types. Regarding patients who are eligible for IO therapies, the most commonly reported challenges were applying pathology results to treatment decisions (29%), differentiating IO therapies (19%), and managing irAEs (19%). Case-based questions revealed gaps in care relative to guidelines: 65% incorrectly identified which patients should be tested for PD-L1; 49% failed to identify the most appropriate IO regimen based on case details; and 65% failed to identify an inappropriate strategy for managing mild irAEs (Table). Further, HCPs reported inappropriate reasons to exclude patients from IO therapy and suboptimal use of supportive care measures. Confidence gaps echoed these challenges; most HCPs reported less-than-high confidence in their ability to apply molecular test results to treatment decisions (80%), differentiate IO therapies based on PD-L1 expression (65%), or coordinate irAE care (85%). Conclusions: In current real-world practice, mNSCLC care teams report challenges in biomarker testing and interpretation; differentiation of IO therapies based on patient, disease, and treatment factors; and irAE management. These identified gaps represent key opportunities for future interventions to improve mNSCLC care. [Table: see text]
Back to the well: Can patients with advanced non-small cell lung cancer benefit from changing PD-1/PD-L1 inhibitors after progression?
Authors: Newman James , Lee Chung-Shien , McGovern Kerri , Seetharamu Nagashree
Published: June 2021

e21194

Background: Immune checkpoint inhibitors (ICIs) have transformed the standard of care of non-small cell lung cancer (NSCLC) and are capable of inducing a sustained response in a cohort of patients. For those who progress while on ICIs and do not have a targetable mutation, options are typically reduced to chemotherapeutic regimens which have a higher probability of toxicity. In patients with a suboptimal performance status or those who are opposed to receiving chemotherapy and are not eligible or interested in clinical trials, treatments are unfortunately limited. Patients who progress on one ICI do not receive a different ICI as part of standard care in subsequent lines of therapy. Data behind switching ICIs, particularly to those with a different mechanism of action (ie anti-PD-1 followed by anti-PD-L1 or vice versa), are lacking. We evaluated the efficacy of receiving a 2nd ICI in patients with NSCLC. Methods: A single-center, IRB-approved retrospective analysis was conducted of NSCLC patients treated with two different ICIs from March 2015 to July 2020. ICIs were given either in combination with chemotherapy or as monotherapy. Patient and tumoral characteristics, including PD-L1 status (if available) and sequence of ICIs, were captured. A positive PD-L1 was defined as PD-L1 expression > 0%. Progression-free survival (PFS) of each ICI (defined as PFS1 and PFS2) were calculated in months (m) for each patient. Median PFS2 was compared between groups stratified by a cutoff median PFS1 of 3m, sequence of PD-1 and PD-L1 inhibitors, and PD-L1 positive and negative subsets. Mood’s median test was used to compare medians. Results: 26 patients were included in the final analysis. 19/26 patients had a PFS1 > 3m. For this cohort, the median PFS2 was 2.5m (Range: 0.1-36.2) compared to median PFS2 of 1.6m (Range: 0.6-15.9) in patients with PFS1 < 3m (p=0.1847). 15 patients received a PD-1 inhibitor followed by a PD-L1 inhibitor. In this subgroup, the median PFS2 was 1.2m (Range: 0.2-36.2). Alternatively, 7 patients received a PD-L1 inhibitor followed by a PD-1 inhibitor and the median PFS2 in this cohort was 2.3m (Range: 0.1-15.9) (p=0.6471). PD-L1 data was available for 19 patients. 8/19 patients with positive PD-L1 had a median PFS2 of 3.6m (Range: 0.2-13.3) compared to median PFS2 of 1.3m (Range: 0.1-36.2) in patients with negative PD-L1 (p=0.2599). Conclusions: Treatment with a 2nd ICI can potentially provide a modest benefit in patients with advanced NSCLC, and some may even experience a very prolonged response. PFS1, sequence of PD-1/PD-L1 inhibitors, and PD-L1 expression did not show any significant correlation with PFS2. Using a 2nd ICI should be considered for advanced NSCLC patients with diminished performance status or limited treatment options.
Spectrum of BRAF mutations in Indian patients with NSCLC: A molecular kaleidoscope.
Authors: Sharma Mansi , Nathany Shrinidhi , Soni Satyajeet , Jain Arpit , Mehta Anurag , Jain Parveen , Batra Ullas
Published: June 2021

e21199

Background: Mutations in the BRAF gene (0.8%-8% cases of NSCLC) comprise a molecularly heterogeneous group, with the canonical V600E mutation as well as myriad variants. Traditionally, diagnostics utilize modalities like mutation specific IHC or allele specific real-time PCR for detection of V600E variant and may underestimate the true prevalence of non-V600E variants. Broader panel next generation sequencing (NGS) testing may be a better modality for detecting them and this may have potential therapeutic implications. This retrospective study of patients with BRAF mutated NSCLC looked at their molecular and clinicopathologic spectrum. Methods: 260 patients underwent panel based NGS testing between 2017-2020. BRAF mutant cases, detected at any point during the course of their disease, were reviewed for clinical, pathologic, molecular features; as well as associated treatment and outcomes. Results: BRAF alterations were seen in 14/260 (5.38%) patients. Median age of the cohort was 62 years (range: 39-86 years) with a female predilection (8/14, 57.1%). BRAF V600E mutation was seen in 6 (42.9%) patients and 8 (57.1%) harbored a non-V600E alteration; the spectrum of which included G466E, G469A, N581I, V600_K601delins, D594G, L597Q, G649V and a TRIM24-BRAF fusion. All patients were never smokers with an adenocarcinoma histology.11 (78.6%) patients had extra thoracic metastases, and 2 (14.3%) cases had metastases to the brain at diagnosis. 11/14 (78.6%) patients had presence of liver metastases (V600E vs non V600E: 43% vs 57%, p = 0.09). 11 patients took treatment at our centre and two patients received anti-BRAF therapy. One patient with V600E mutation received vemurafenib. The other patient with a nonV600E mutation (V600_601delins, detected on NGS) received combination dabrafenib-trametinib with an ongoing partial response at 6 months. 8 patients received chemotherapy and median PFS was 4.8 months, similar for all mutation types. Median OS for the entire cohort was not reached owing to high censorship. Conclusions: This single centre study depicts distinct clinicopathologic features in Indian patients with BRAF mutant NSCLC. The higher prevalence of non-V600E mutation may be attributed to increased use of broader panel based NGS testing as opposed to sequential single gene testing. One of the patients with a non-V600E mutation responded to targeted therapy, hence clinicians should be aware of this spectrum of potentially targetable BRAF mutations.
Overweight or obese patients may take longer to respond and be less responsive to immune checkpoint inhibitors in non-small cell lung cancer: A retrospective review.
Authors: Palmer John P. , Cao Yenong , Ibrahim Samer , Dhawan Natasha , Afzal Muhammad Zubair , Shirai Keisuke
Published: June 2021

e21209

Background: Immune checkpoint inhibitors (ICI) are now the standard of care in the treatment of non-small cell lung cancer (NSCLC). ICIs may be used as monotherapy or in combination with chemotherapy. Increased recruitment of inflammatory cells in the tumor micro-environment is associated with a poor response to ICIs. Although obesity is a risk factor for many types of cancers, including lung cancer, it is associated with a low systemic inflammation state. This creates an effect known as the “obesity paradox,” resulting in better treatment-related outcomes in overweight and obese patients receiving ICIs. However, in obese patients, the neutralizing interleukin (IL) - 1β level is high, which can decrease the responsiveness to ICI. We aim to study the effect of increased weight on treatment-related outcomes in NSCLC patients receiving ICI. Methods: We conducted a retrospective analysis on 178 NSCLC patients treated with ICIs, such as pembrolizumab, nivolumab, ipilimumab/nivolumab or atezolizumab, alone or in combination with chemotherapy. Overweight was defined as having a BMI of 25 – 29.9 while obesity was defined as having a BMI of ≥ 30. Overall survival (OS), progression free survival (PFS), best radiographic response, and the time to achieve radiographic response were evaluated. Cox regression univariate and multivariate analyses were performed. Logistic regression and Chi-square tests were applied. Results: Of the 178 patients with NSCLC, 81% had adenocarcinoma, and 19% had squamous, adenosquamous, or large cell carcinoma. The majority of patients were female (56.2% vs. 43.8%). Overall, 48.6% patients were overweight or obese. The objective response rate (ORR) was 45.1% and the disease control rate (DCR) was 75.8%. The ORR was 37% in overweight/obese patients compared to 52% in patients with a normal weight (p = 0.06). The DCR was 76% vs. 73.9%, (p = 0.7). The median time to achieve the best radiographic response was 3.7 months in overweight/obese patients compared to 2.5 months in those of normal weight (p = 0.2). A considerably higher proportion of the patients progressed in overweight/obese category (80.7% vs. 69.3%, P = 0.08). However, there was no significant difference in median PFS between the two categories (7.4 vs. 8.1 months, P = 0.2). The overall survival was not significant different between both categories (15.9 vs. 16.8 months, P = 0.5). Conclusions: Our study suggests that obesity and overweight status can result in a low response rate to ICIs in NSCLC patients and can delay the time to achieve the best radiographic response per RECIST criteria. However, we did not observe any significant impact on the overall or progression-free survival. A large, population-based study will help to elucidate the impact of weight on the responsiveness to ICI.