Phase I/II trial of plinabulin in combination with nivolumab and ipilimumab in patients with recurrent small cell lung cancer (SCLC): Big ten cancer research consortium (BTCRC-LUN17-127) study.

BACKGROUND: Plinabulin is a GEF-H1 releasing agent with an immune-enhancing function. We report results from a multicenter Phase I/II study (NCT03575793) assessing plinabulin in combination with nivolumab and ipilimumab for the treatment of recurrent SCLC. METHODS: In Phase I, patients were enrolled using a 3 + 3 design to determine dose-limiting toxicities (DLTs) and recommended Phase 2 dose (RP2D). Patients received nivolumab (1 mg/kg), ipilimumab (3 mg/kg), and plinabulin (in escalating doses) on day 1 of each 21-day cycle for 4 cycles followed by maintenance with plinabulin and nivolumab. In phase II, patients with recurrent PD(L)1 inhibitor resistant SCLC were enrolled. The primary objective was median progression-free survival (PFS). RESULTS: Between 9/2018 and 2/2023, 39 patients were enrolled, and 36 patients received study treatment and were evaluable for safety (16 in Phase I; 20 in Phase II). In the phase I dose-escalation, there were 2 DLTs; grade 3 altered mental status lasting <24 h and grade 3 infusion reaction. The Plinabulin RP2D was determined to be 30 mg/m2. Common TRAEs were vomiting (44 %), nausea (42 %), and infusion reaction (36 %); 6 % of patients had a ≥grade 3 TRAE. Five patients (14 %) had ≥grade 3 irAEs; there were no cases of immune-related pneumonitis. In the efficacy analysis in 27 patients, the median PFS was 1.6 months (95 % CI 1.2 to 2.7) and the trial did not meet the pre-specified target median PFS of 3.5 months. Four patients treated at 30 mg/m2 had PR (confirmed 1, unconfirmed 3); 5 patients had SD with a CBR of 33 %. Two of 8 patients treated in phase I at the lower 20 mg/m2 dose had confirmed PR, with 1 patient on the drug regimen for >90 cycles. The median OS and follow-up time were 5.5 months and 2.5 months respectively. CONCLUSIONS: Plinabulin in combination with nivolumab and ipilimumab was tolerable at the dose of 30 mg/m2. While the clinical responses in PD-1 resistant SCLC were limited, some patients had a long duration of response. The number of ≥grade 3 irAE with the combination were lower than expected.

Neighborhood-level deprivation and survival in lung cancer.

BACKGROUND: Despite recent advances in lung cancer therapeutics and improving overall survival, disparities persist among socially disadvantaged populations. This study aims to determine the effects of neighborhood deprivation indices (NDI) on lung cancer mortality. This is a multicenter retrospective cohort study assessing the relationship between NDI and overall survival adjusted for age, disease stage, and DNA methylation among biopsy-proven lung cancer patients. State-specific NDI for each year of sample collection were computed at the U.S. census tract level and dichotomized into low- and high-deprivation. RESULTS: A total of 173 non small lung cancer patients were included, with n = 85 (49%) and n = 88 (51%) in the low and high-deprivation groups, respectively. NDI was significantly higher among Black patients when compared with White patients (p = 0.003). There was a significant correlation between DNA methylation and stage for HOXA7, SOX17, ZFP42, HOXA9, CDO1 and TAC1. Only HOXA7 DNA methylation was positively correlated with NDI. The high-deprivation group had a statistically significant shorter survival than the low-deprivation group (p = 0.02). After adjusting for age, race, stage, and DNA methylation status, belonging to the high-deprivation group was associated with higher mortality with a hazard ratio of 1.81 (95%CI: 1.03-3.19). CONCLUSIONS: Increased neighborhood-level deprivation may be associated with liquid biopsy DNA methylation, shorter survival, and increased mortality. Changes in health care policies that consider neighborhood-level indices of socioeconomic deprivation may enable a more equitable increase in lung cancer survival.

Disparities in outcomes between Black and White patients in North America with thoracic malignancies and COVID-19 infection (TERAVOLT).

BACKGROUND: Patients with thoracic malignancies who develop COVID-19 infection have a higher hospitalization rate compared to the general population and to those with other cancer types, but how this outcome differs by race and ethnicity is relatively understudied. METHODS: The TERAVOLT database is an international, multi-center repository of cross-sectional and longitudinal data studying the impact of COVID-19 on individuals with thoracic malignancies. Patients from North America with thoracic malignancies and confirmed COVID-19 infection were included for this analysis of racial and ethnic disparities. Patients with missing race data or races and ethnicities with fewer than 50 patients were excluded from analysis. Multivariable analyses for endpoints of hospitalization and death were performed on these 471 patients. RESULTS: Of the 471 patients, 73% were White and 27% were Black. The majority (90%) were non-Hispanic ethnicity, 5% were Hispanic, and 4% were missing ethnicity data. Black patients were more likely to have an Eastern Cooperative Oncology Group (ECOG) Performance Status ≥ 2 (p-value = 0.04). On multivariable analysis, Black patients were more likely than White patients to require hospitalization (Odds Ratio (OR): 1.69, 95% CI: 1.01-2.83, p-value = 0.044). These differences remained across different waves of the pandemic. However, no statistically significant difference in mortality was found between Black and White patients (OR 1.29, 95% CI: 0.69-2.40, p-value = 0.408). CONCLUSIONS: Black patients with thoracic malignancies who acquire COVID-19 infection are at a significantly higher risk of hospitalization compared to White patients, but there is no significant difference in mortality. The underlying drivers of racial disparity among patients with thoracic malignancies and COVID-19 infection require ongoing investigation.

Clinical characteristics, racial inequities, and outcomes in patients with breast cancer and COVID-19: A COVID-19 and cancer consortium (CCC19) cohort study.

Background: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. Methods: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. Results: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. Conclusions: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. Funding: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. Clinical trial number: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701.

Direct Oral Anticoagulants vs Low-Molecular-Weight Heparin and Recurrent VTE in Patients With Cancer: A Randomized Clinical Trial.

Importance: In patients with cancer who have venous thromboembolism (VTE) events, long-term anticoagulation with low-molecular-weight heparin (LMWH) is recommended to prevent recurrent VTE. The effectiveness of a direct oral anticoagulant (DOAC) compared with LMWH for preventing recurrent VTE in patients with cancer is uncertain. Objective: To evaluate DOACs, compared with LMWH, for preventing recurrent VTE and for rates of bleeding in patients with cancer following an initial VTE event. Design, Setting, and Participants: Unblinded, comparative effectiveness, noninferiority randomized clinical trial conducted at 67 oncology practices in the US that enrolled 671 patients with cancer (any invasive solid tumor, lymphoma, multiple myeloma, or chronic lymphocytic leukemia) who had a new clinical or radiological diagnosis of VTE. Enrollment occurred from December 2016 to April 2020. Final follow-up was in November 2020. Intervention: Participants were randomized in a 1:1 ratio to either a DOAC (n = 335) or LMWH (n = 336) and were followed up for 6 months or until death. Physicians and patients selected any DOAC or any LMWH (or fondaparinux) and physicians selected drug doses. Main Outcomes and Measures: The primary outcome was the recurrent VTE rate at 6 months. Noninferiority of anticoagulation with a DOAC vs LMWH was defined by the upper limit of the 1-sided 95% CI for the difference of a DOAC relative to LMWH of less than 3% in the randomized cohort that received at least 1 dose of assigned treatment. The 6 prespecified secondary outcomes included major bleeding, which was assessed using a 2.5% noninferiority margin. Results: Between December 2016 and April 2020, 671 participants were randomized and 638 (95%) completed the trial (median age, 64 years; 353 women [55%]). Among those randomized to a DOAC, 330 received at least 1 dose. Among those randomized to LMWH, 308 received at least 1 dose. Rates of recurrent VTE were 6.1% in the DOAC group and 8.8% in the LMWH group (difference, -2.7%; 1-sided 95% CI, -100% to 0.7%) consistent with the prespecified noninferiority criterion. Of 6 prespecified secondary outcomes, none were statistically significant. Major bleeding occurred in 5.2% of participants in the DOAC group and 5.6% in the LMWH group (difference, -0.4%; 1-sided 95% CI, -100% to 2.5%) and did not meet the noninferiority criterion. Severe adverse events occurred in 33.8% of participants in the DOAC group and 35.1% in the LMWH group. The most common serious adverse events were anemia and death. Conclusions and Relevance: Among adults with cancer and VTE, DOACs were noninferior to LMWH for preventing recurrent VTE over 6-month follow-up. These findings support use of a DOAC to prevent recurrent VTE in patients with cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02744092.

Clinical Characteristics, Racial Inequities, and Outcomes in Patients with Breast Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Cohort Study.

Background: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. Methods: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. Results: 1,383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32 - 1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70 - 6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83 - 12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63 - 3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20 - 2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66 - 3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89 - 22.6]). Hispanic ethnicity, timing and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. Conclusions: Using one of the largest registries on cancer and COVID-19, we identified patient and BC related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to Non-Hispanic White patients.

Myo1e overexpression in lung adenocarcinoma is associated with increased risk of mortality.

This study aims to perform a comprehensive genomic analysis to assess the influence of overexpression of MYO1E in non-small cell lung carcinoma (NSCLC) and whether there are differences in survival and mortality risk in NSCLC patients depending on both DNA methylation and RNA expression of MYO1E. The DNA methylation probe cg13887966 was inversely correlated with MYO1E RNA expression in both LUAD and LUSC subpopulations showing that lower MYO1E RNA expression was associated with higher MYO1E DNA methylation. Late stages of lung cancer showed significantly lower MYO1E DNA methylation and significantly higher MYO1E RNA expression for LUAD but not for LUSC. Low DNA methylation as well as high RNA expression of MYO1E are associated with a shorter median survival time and an increased risk of mortality for LUAD, but not for LUSC. This study suggests that changes in MYO1E methylation and expression in LUAD patients may have an essential role in lung cancer's pathogenesis. It shows the utility of MYO1E DNA methylation and RNA expression in predicting survival for LUAD patients. Also, given the low normal expression of MYO1E in blood cells MYO1E DNA methylation has the potential to be used as circulating tumor marker in liquid biopsies.

Oncology distress screening within predominately Black Veterans: Outcomes on supportive care utilization, hospitalizations, and mortality.

BACKGROUND: We evaluated whether patients' initial screening symptoms were related to subsequent utilization of supportive care services and hospitalizations, and whether patient-level demographics, symptoms, hospitalizations, and supportive care service utilization were associated with mortality in primarily low-income, older, Black Veterans with cancer. METHODS: This quality improvement project created collaborative clinics to conduct cancer distress screenings and refer to supportive care services at an urban, VA medical center. All patients completed a distress screen with follow-up screening every 3 months. Supportive care utilization, hospitalization rates, and mortality were abstracted through medical records. Poisson regression models and cox proportional hazard models were utilized. RESULTS: Five hundred and eighty five screened patients were older (m = 72), mostly Black 70% (n = 412), and had advanced cancer 54%. Fifty-eight percent (n = 340) were screened only once with 81% (n = 470) receiving ≥1 supportive care service and 51.5% (n = 297) being hospitalized ≥1 time 18 months following initial screen. Symptom severity was significantly related to number of hospitalizations. Low mood was significantly related to higher supportive services (p < 0.001), but not hospitalizations (p ≥ 0.52). Pain, fatigue, physical function, nutrition, and physical symptoms were significantly associated with more supportive services and hospitalizations (p < 0.01). Twenty percent (n = 168) died; Veterans who were Black, had lower stage cancers, better physical health, and utilized less supportive care services had lower odds of mortality (p ≤ 0.01). CONCLUSION: Individuals with elevated distress needs and those reporting lower physical function utilized more supportive care services and had higher hospitalization rates. Lower physical function, greater supportive care use, higher stage cancer, and being non-Black were associated with higher odds of death.

Increased Utilization of Stereotactic Body Radiotherapy is Associated with Decreased Disparities and Improved Survival for Early-Stage NSCLC.

INTRODUCTION: We sought to determine if increased use of stereotactic body radiation therapy (SBRT) was associated with decreased disparities in the receipt of definitive treatment for early-stage non-small cell lung cancer (NSCLC). METHODS: The National Cancer Database (NCDB) was utilized to determine the proportion of patients with NSCLC receiving surgery, SBRT, or no definitive treatment for clinical cT1-2aN0M0 NSCLC from 2004-2017. Univariable and multivariable logistic regressions were used. Age-adjusted mortality rates were calculated using the Surveillance, Epidemiology, and End Result (SEER) database. RESULTS: From 2004 to 2017, the proportion of early-stage NSCLC undergoing no definitive treatment declined from 22% to 10.5% (P<.001), while the proportion receiving SBRT increased from 1% (0.9%-1.3%) to 22% (21.4%-22.3%; P<.001). Among Whites, the proportion undergoing no definitive treatment decreased from 21% to 10% (P<.001), as compared to Blacks, which had a higher decrease, of 32% to 15% (P<.001). The proportion of Blacks receiving SBRT increased from 1% (0.3%-1.7%) to 22% (20.8%-23.5%) (P<.001). Between 2011 and 2017 likelihood of Blacksreceiving curative therapy increased compared to Whites [OR: 0.55 (0.48-0.64) to 0.70 (0.62-0.79; P<.001]. Furthermore, the age-adjusted mortality rate of early-stage NSCLC decreased from 4.3 (4.0-4.5) in 2004 to 0.8 (0.7-0.9) in 2017 (P<.001). CONCLUSIONS: Increased utilization of SBRT significantly increased the proportion of patients receiving curative therapy for early-stage NSCLC and was associated with an improvement in mortality.  Furthermore, the use of SBRT reduced previously seen disparities in receipt of treatment between Whites and Blacks. SBRT was also associated with decreased mortality from early-stage NSCLC.

A phase 2 trial of chemotherapy plus pembrolizumab in patients with advanced non-small cell lung cancer previously treated with a PD-1 or PD-L1 inhibitor: Big Ten Cancer Research Consortium BTCRC-LUN15-029.

BACKGROUND: Immunotherapy using a checkpoint inhibitor (CPI) alone or in combination with chemotherapy is the standard of care for treatment-naive patients with advanced non-small cell lung cancer (NSCLC) without driver mutations for which targeted therapies have been approved. It is unknown whether continuing CPI treatment beyond disease progression results in improved outcomes. METHODS: Patients who experienced progressive disease (PD) after a clinical benefit from chemotherapy plus a CPI were enrolled. Patients received pembrolizumab (200 mg every 3 weeks) plus next-line chemotherapy. The primary end point was progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Key secondary end points included the overall survival (OS), clinical benefit rate, and toxicity. The authors' hypothesis was that continuing pembrolizumab beyond progression would improve the median PFS to 6 months in comparison with a historical control of 3 months with single-agent chemotherapy alone. RESULTS: Between May 2017 and February 2020, 35 patients were enrolled. The patient and disease characteristics were as follows: 51.4% were male; 82.9% were current or former smokers; and 74.3%, 20%, and 5.7% had adenocarcinoma, squamous cell carcinoma, and NSCLC not otherwise specified, respectively. The null hypothesis that the median PFS would be 3 months was rejected (p < .05). The median PFS was 5.1 months (95% confidence interval [CI], 3.6-8.0 months). The median OS was 24.5 months (95% CI, 15.6-30.9 months). The most common treatment-related adverse events were fatigue (60%), anemia (54.3%), and nausea (42.9%). There were no treatment-related deaths. CONCLUSIONS: Pembrolizumab plus next-line chemotherapy in patients with advanced NSCLC who experienced PD after a clinical benefit from a CPI was associated with statistically significant higher PFS in comparison with historical controls of single-agent chemotherapy alone.

A Randomized Multi-institutional Phase II Trial of Everolimus as Adjuvant Therapy in Patients with Locally Advanced Squamous Cell Cancer of the Head and Neck.

PURPOSE: Investigate whether adjuvant everolimus, an mTOR inhibitor, improves progression-free survival (PFS) in advanced-stage head and neck squamous cell carcinoma (HNSCC) and provide outcomes related to correlative biological factors associated with disease control. PATIENTS AND METHODS: This was a prospective, randomized, double-blind phase II trial of patients with advanced-stage HNSCC from 13 institutions who were confirmed disease-free post-definitive therapy and enrolled between December 2010 and March 2015. Patients received adjuvant everolimus or placebo daily (10 mg, oral) for a maximum of 1 year. p16 IHC as a surrogate marker for human papillomavirus infection and whole-exome sequencing were performed. Cox proportional hazard models estimated hazard rates. Log-rank tests evaluated differences in survival. The primary endpoint was PFS. Secondary endpoints and objectives included overall survival (OS) and toxicity assessment. RESULTS: 52 patients [median (range) age, 58 (37-76) years; 43 men (83%), 9 women (17%)] were randomized to placebo (n = 24) or everolimus (n = 28). PFS favored everolimus, but was not significant [log-rank P = 0.093; HR = 0.44; 95% confidence interval (CI), 0.17-1.17]. There was no difference in OS (P = 0.29; HR = 0.57; 95% CI, 0.20-16.2). Everolimus resulted in significant improvement in PFS for p16-negative patients (n = 31; P = 0.031; HR = 0.26; 95% CI, 0.07-0.97), although subgroup analysis showed no difference for p16-positive patients (n = 21; P = 0.93). Further, PFS was significantly higher in TP53-mutated (TP53mut) patients treated with everolimus compared with placebo (log-rank P = 0.027; HR = 0.24; 95% CI, 0.06-0.95). No treatment difference was seen in patients with TP53 wild-type tumors (P = 0.79). CONCLUSIONS: p16-negative and TP53mut patients may benefit from adjuvant treatment with everolimus.

Surgery for early-stage lung cancer with video-assisted thoracoscopic surgery versus open thoracotomy: A narrative review.

Recommending video-assisted thoracic surgery (VATS) over open thoracotomy to patients with early-stage non-small-cell lung cancer (NSCLC) is controversial. Accordingly, we reviewed randomized comparative studies to determine the risks and benefits of VATS lobectomy. Electronic searches on PubMed with standard search terms revealed 97 comparative studies published between 1990 and 2022. Of those, only 5 were randomized controlled clinical trials (RCT) and 1 is still ongoing although initial data has been published as an abstract form. A total of 918 patients were evaluated in 5 RCT's. All studies included patients with known or suspected primary lung cancer randomized in a 1:1 ratio to VATS or thoracotomy. Between 2 studies, reports of 1-year, 3-year and 5-year overall survival were found to be similar across surgical modalities. Additionally, no differences were found in the rates of locoregional and distant recurrence. Three studies reported no statistical differences in the number of hilar and mediastinal lymph nodes sampled. Two studies found decreased length of stay following VATS (4 days v 5 days, P = 0.027 and P = 0.008), while 2 found no difference. Increased in-hospital complications were seen in 2 studies (P = 0.008 and P = 0.039). VATS was associated with decreased pain scores, better self-reported QOL at 52 weeks (P = 0.014). Few randomized clinical trials comparing VATS lobectomy to open thoracotomy and lobectomy in early stage NSCLC have been reported. These studies suggest that VATS lobectomy offers similar outcomes with decreased in-hospital complications, pain, length of stay, and improved physical functioning when compared to thoracotomy.

Impact of CT screening in lung cancer: Scientific evidence and literature review.

The treatment of lung cancer has improved significantly in recent years however, lung cancer remains as a leading cause of cancer-related mortality worldwide. Lung cancer screening has been explored, over the past several decades, as a means of reducing lung cancer mortality, to identify asymptomatic disease when it is potentially curable. The National Lung Screening Trial (NLST) established that low-dose computed tomography (LDCT) scans of the chest can be instrumental in reducing lung cancer mortality but the criteria for screening implemented in this trial may not be equitably sensitive across racial and sex subpopulations. Furthermore, the high false detection rate reported in this trial has raised concerns regarding overdiagnosis with LDCT alone. The aim of this review is to summarize the history of lung cancer screening trials, limitations of lung cancer screening, the impact of alternative risk prediction models in reducing disparities, and the use of biomarkers in conjunction with imaging to improve diagnostic authenticity.

A Phase II Trial of Atezolizumab Plus Carboplatin Plus Pemetrexed Plus Bevacizumab in the Treatment of Patients with Stage IV Non-Squamous Non-Small Cell Lung Cancer: Big Ten Cancer Research Consortium (BTCRC)- LUN 17-139.

INTRODUCTION: LUN17-139 evaluated the safety and efficacy of Atezolizumab (A) plus Carboplatin (C) plus Pemetrexed (Pem) plus Bevacizumab (B) (ACBPem) in treatment naïve patients with stage IV non-squamous non-small cell lung cancer (Ns-NSCLC). PATIENTS AND METHODS: In this multicenter, single-arm phase II trial, all patients received A (1200-mg, D1) + C (AUC 5, D1) + Pem (500-mg/m2, D1) + B (15-mg/kg D1) q3 week x4. If no PD (progressive disease), patients received maintenance ABPem until PD or intolerable side effects. The primary endpoint was progression-free survival (PFS). The positive PFS result was considered as PFS>6m (historical control). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) defined by complete response (CR) + partial response (PR) + stable disease (SD) ≥ 2 months, overall survival (OS), and safety. RESULTS: Thirty patients were enrolled from November 2018 to October 2020. The study was closed early due to 3 patient deaths, possibly related to treatment. Median age 64 (range 38-83); Men/Women 20/10; PD-L1 TPS < 1%/1-49%/ ≥ 50% (8/15/7). The median follow-up was 20.3 months ( 1-28.1). ORR 42.9% (95% CI, 24.5-62.8%), DCR 96.4% (95% CI, 81.7-99.9%). The median PFS and OS were 11.3m (5.5-14.9,P > .05) and 22.4m (22.4-NR), respectively. Four patients had G4 toxicity (anemia, febrile-neutropenia, severe neutropenia, sepsis), and 3 patients had G5 toxicity (thromboembolism, sepsis, colonic perforation). CONCLUSION: ABCPem was associated with increased PFS compared to historical controls but this difference did not meet the statistical significance. Three on-treatment deaths and 5 thromboembolic events prompted early closure.

Coinfections in Patients With Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Study.

BACKGROUND: The frequency of coinfections and their association with outcomes have not been adequately studied among patients with cancer and coronavirus disease 2019 (COVID-19), a high-risk group for coinfection. METHODS: We included adult (≥18 years) patients with active or prior hematologic or invasive solid malignancies and laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection, using data from the COVID-19 and Cancer Consortium (CCC19, NCT04354701). We captured coinfections within ±2 weeks from diagnosis of COVID-19, identified factors cross-sectionally associated with risk of coinfection, and quantified the association of coinfections with 30-day mortality. RESULTS: Among 8765 patients (hospitalized or not; median age, 65 years; 47.4% male), 16.6% developed coinfections: 12.1% bacterial, 2.1% viral, 0.9% fungal. An additional 6.4% only had clinical diagnosis of a coinfection. The adjusted risk of any coinfection was positively associated with age >50 years, male sex, cardiovascular, pulmonary, and renal comorbidities, diabetes, hematologic malignancy, multiple malignancies, Eastern Cooperative Oncology Group Performance Status, progressing cancer, recent cytotoxic chemotherapy, and baseline corticosteroids; the adjusted risk of superinfection was positively associated with tocilizumab administration. Among hospitalized patients, high neutrophil count and C-reactive protein were positively associated with bacterial coinfection risk, and high or low neutrophil count with fungal coinfection risk. Adjusted mortality rates were significantly higher among patients with bacterial (odds ratio [OR], 1.61; 95% CI, 1.33-1.95) and fungal (OR, 2.20; 95% CI, 1.28-3.76) coinfections. CONCLUSIONS: Viral and fungal coinfections are infrequent among patients with cancer and COVID-19, with the latter associated with very high mortality rates. Clinical and laboratory parameters can be used to guide early empiric antimicrobial therapy, which may improve clinical outcomes.

Increased Disparities in Patients Diagnosed with Metastatic Lung Cancer Following Lung CT Screening in the United States.

OBJECTIVES: We sought to determine if implementation of low dose computed tomography (LDCT) screening for lung cancer in the United States had led to changes in patients being diagnosed with metastatic lung cancer over time. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Result (SEER) database was utilized to determine the proportion of lung cancers diagnosed as stage I to III and stage IV from 2009-2018. Changes in lung cancer stage distribution were compared in the overall population and by race. RESULTS: From 2009 to 2018, the proportion of stage I to III lung cancers increased from 52% (51.3%-53.2%) in 2009 to 56% (54.0%-55.8%) in 2018 (P < .001). Correspondingly, the proportion of lung cancers diagnosed in stage IV decreased from 48% (46.8%-48.7%) in 2009 to 45% (44.2%-46.0%) (P < .001) in 2018. For white patients, the proportion increased from 53% (51.6%-53.7%) to 56% (55.1%-57.1%) (P < .001). However, for black patients, no trend was present, with the proportion being 51% (47.9%-53.4%) in 2009 and 52% (49.0%-54.2%) in 2018 (P = .303). CONCLUSION: Since the implementation of LDCT screening, the proportion of early-stage lung cancers increased in the general population. These changes in stage distribution were not present in black patients.

Addressing Sex Disparities in Lung Cancer Screening Eligibility: USPSTF vs PLCOm2012 Criteria.

BACKGROUND: Lung cancer is the leading cause of cancer death in women in the United States. Prospective randomized lung screening trials suggest a greater lung cancer mortality benefit from screening women compared with men. RESEARCH QUESTION: Do the United States Preventative Services Task Force (USPSTF) lung screening guidelines that are based solely on age and smoking history contribute to sex disparities in eligibility, and if so, does the use of the PLCOm2012 risk prediction model that is based on 11 predictors of lung cancer reduce sex disparities? STUDY DESIGN AND METHODS: This retrospective analysis of 883 lung cancer cases in the Chicago Race Eligibility for Screening Cohort (CREST) determined the sensitivity of USPSTF vs PLCOm2012 eligibility criteria, stratified according to sex. For comparisons vs the USPSTF 2013 and the recently published USPSTF 2021 (released March 9, 2021) eligibility criteria, the PLCOm2012 model was used with risk thresholds of ≥ 1.7%/6 years (6y) and ≥ 1.0%/6y, respectively. RESULTS: The sensitivities for screening by the USPSTF 2013 were 46.7% for women and 64.6% for men (P = .003) and by the USPSTF 2021 were 56.8% and 71.8%, respectively (P = .02). In contrast, the PLCOm2012 ≥ 1.7%/6y sensitivities were 64.6% and 70.4%, and the PLCOm2012 ≥ 1.0%/6y sensitivities were 77.4% and 82.4%. The PLCOm2012 differences in sensitivity using ≥ 1.7%/6y and ≥ 1.0%/6y thresholds between women and men were nonsignificant (both, P = .07). Compared with men, women were more likely to be ineligible according to the USPSTF 2021 criteria because their smoking exposures were < 20 pack-years (22.8% vs 14.8%; ORWomen vs Men, 1.70; 95% CI, 1.19-2.44; P = .002), and 27% of these ineligible women were eligible according to the PLCOm2012 ≥ 1.0%/6y criteria. INTERPRETATION: Although the USPSTF 2021 eligibility criteria are more sensitive than the USPSTF 2013 guidelines, sex disparities in eligibility remain. Adding the PLCOm2012 risk prediction model to the USPSTF guidelines would improve sensitivity and attenuate sex disparities.

Severe Psychiatric Symptoms in a Patient With EGFR Exon-20 Insertion Mutation Receiving Mobocertinib: A Case Report.

Tyrosine kinase inhibitor therapy is an established standard of care for patients with NSCLC with EGFR mutations, but a worse prognosis has been observed in patients with specific EGFR exon-20 insertion mutations. Mobocertinib (TAK-788) is a novel tyrosine kinase inhibitor developed to target EGFR exon-20 insertion and has exhibited promising response rates and acceptable safety in phase 1 and 2 trials. We report a case of a 59-year-old woman with metastatic NSCLC and EGFR exon-20 mutation responsive to mobocertinib therapy, who developed severe depression and catatonia approximately 4 months after mobocertinib initiation, ultimately necessitating its permanent discontinuation. Given the observed severe depression in this case report, we recommend that, for patients on mobocertinib who develop neuropsychiatric adverse effects, strong consideration should be given for dose interruption or discontinuation.

Brief Report: Risk Prediction Model Versus United States Preventive Services Task Force 2020 Draft Lung Cancer Screening Eligibility Criteria-Reducing Race Disparities.

INTRODUCTION: Eligibility criteria for lung cancer screening based solely on age and smoking history are less sensitive than validated risk prediction models. The U.S. Preventive Services Task Force (USPSTF) has proposed new guidelines to improve the sensitivity for selecting high-risk individuals and to decrease race disparity. In this retrospective study, termed the Chicago Race Eligibility for Screening Cohort, we compare the sensitivity of the proposed USPSTF2020 criteria versus the PLCOm2012 risk prediction model for selecting a racially diverse lung cancer population with a smoking history for lung cancer screening. METHODS: This Chicago Race Eligibility for Screening Cohort study applies the PLCOm2012 model with a risk threshold of 1.0%/6 years and the USPSTF2020 criteria (age 50-80 y, pack-years ≥ 20 y, quit-years ≤ 15 y) to 883 individuals with a smoking history diagnosed with having lung cancer. RESULTS: The PLCOm2012 was more sensitive than the USPSTF2020 overall (79.1% versus 68.6%, p < 0.0001) in White (81.5% versus 75.4%, p = 0.029) and in African American (82.8% versus 70.6% p < 0.0001) individuals. Of the total cohort, 254 (28.8%) would not have qualified owing to less than 20 pack-years, quit-time of more than 15 years, and age less than 50 years. Of these 254 cases, 40% would have qualified by the PLCOm2012 model. For the 20 pack-year criterion, of the 497 African American individuals, 19.3% did not meet this criterion, and of these, an additional 31.3% would have qualified by the PLCOm2012 model (p = 0.002). CONCLUSIONS: Although more sensitive than USPSTF2013, the proposed USPSTF2020 draft guidelines still have a race disparity in eligibility for screening. This study provides "real world" evidence that use of the PLCOm2012 risk prediction model eliminates this race disparity.

Outcomes of patients with stage III non-small cell lung cancer (NSCLC) that harbor a STK11 mutation.

BACKGROUND: STK11 mutation (STK11m ) in patients (pts) with stage IV non-small cell lung cancer (NSCLC) is associated with inferior survival and poor response to immune checkpoint inhibitors (ICI). The significance of STK11m in stage III NSCLC pts treated with concurrent chemoradiation (CCRT) with or without consolidation ICI is unknown. METHODS: Stage III NSCLC patients who received CCRT and had known STK11 mutational status were included in this retrospective study. The data on the STK11m pts were collected from 4 cancer institutions. A cohort of pts with wild type STK11 (STK11w ) from the University of Iowa served as a comparison group. Patient demographics and clinical characteristics were collected. Cox regression models were used to explore the effect of STK11 mutation on survival. RESULTS: 75 pts with stage III NSCLC who had known STK11 mutational status were identified. 16/75 (21%) had STK11m . 5/16 with STK11 m did not receive CCRT so they were excluded from the analysis. The clinical and demographic characteristics for the 11 STK11m and 59 STK11w pts were not statistically different (STK11m vs. STK11w ): mean age: 57 vs. 64 yrs, non-squamous histology: 8/11 (73%) vs. 37/59 (63%), KRAS mutation: 3/11 (27%) vs. 11/59 (19%), TP53 mutation: 6/11 (55%) vs. 15/59 (25%), PD-L1 ≥50%: 1/8 (13%) vs. 10/32 (31%), and consolidation ICI 6/11 (55%) vs. 17/59 (29%). Regarding the 6 STK11m pts who received ICI (4 pembrolizumab, 2 durvalumab), the median number of ICI infusions was 8 (range, 3-17) vs. 6 (range, 1-25) in the 17 pts with STK11w who received ICI (durvalumab). After adjusting for performance status and cancer stage, multivariable analysis showed that progression free survival (PFS) for the STK11m pts was significantly worse than STK11 w pts (HR =2.25; 95% CI, 1.03-4.88, P=0.04), whereas overall survival (OS) showed no significant difference for STK11m vs. STK11w patients (HR 1.47, 95% CI, 0.49-4.38, P=0.49). CONCLUSIONS: In stage III NSCLC patients who received CCRT, STK11m was associated with worse PFS compared to STK11w . Larger studies are needed to further explore the prognostic implications of STK11m in stage III NSCLC and whether ICI impacts survival for this subgroup.