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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported .Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3, has shown durable anticancer activity and manageable safety in previously treated small cell lung cancer (SCLC) in DeLLphi-300 phase I and DeLLphi-301 phase II trials. Here, we report extended follow-up of DeLLphi-300 (median follow-up, 12.1 months [range, 0.2-34.3]) in fully enrolled cohorts treated with tarlatamab ≥10 mg dose administered once every two weeks, once every three weeks, or once on day 1 and once on day 8 of a 21-day cycle (N = 152). Overall, the objective response rate (ORR) was 25.0%; the median duration of response (mDOR) was 11.2 months (95% CI, 6.6 to 22.3), and the median overall survival (mOS) was 17.5 months (95% CI, 11.4 to not estimable [NE]). Among 17 patients receiving 10 mg tarlatamab once every two weeks, the ORR was 35.3%, the mDOR was 14.9 months (95% CI, 3.0 to NE), the mOS was 20.3 months (95% CI, 5.1 to NE), and 29.4% had sustained disease control with time on treatment ≥52 weeks. No new safety signals were identified. In modified Response Assessment in Neuro-Oncology Brain Metastases analyses, CNS tumor shrinkage of ≥30% was observed in 62.5% of patients (10 of 16) who had a baseline CNS lesion of ≥10 mm, including in a subset of patients with tumor shrinkage long after previous brain radiotherapy. In DeLLphi-300 extended follow-up, tarlatamab demonstrated unprecedented survival and potential findings of intracranial activity in previously treated SCLC.

Background : Despite advances in targeted therapies and immunotherapies, traditional treatments like microtubule stabilizers (paclitaxel, docetaxel), DNA-intercalating platinum drugs (cisplatin), and radiation therapy remain essential for managing locally advanced and metastatic lung cancer. Identifying novel molecular targets could enhance the efficacy of these treatments. Hypothesis : We hypothesize that BUB1 (Ser/Thr kinase) is overexpressed in lung cancers and its inhibition will sensitize lung cancers to chemoradiation. Methods : BUB1 inhibitor (BAY1816032) was combined with cisplatin, paclitaxel, a PARP inhibitor olaparib, and radiation in cell proliferation and radiation-sensitization assays. Biochemical and molecular assays evaluated the impact on DNA damage signaling and cell death. Results : Immunostaining of lung tumor microarrays (TMAs) confirmed higher BUB1 expression in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) compared to normal tissues. In NSCLC, BUB1 overexpression correlated directly with the expression of TP53 mutations and poorer overall survival in NSCLC and SCLC patients. BAY1816032 synergistically sensitized lung cancer cell lines to paclitaxel and olaparib and enhanced cell killing by radiation in both NSCLC and SCLC. Molecular analysis indicated a shift towards pro-apoptotic and anti-proliferative states, evidenced by altered BAX, BCL2, PCNA, and Caspases-9 and -3 expressions. Conclusions : Elevated BUB1 expression is associated with poorer survival in lung cancer. Inhibiting BUB1 sensitizes NSCLC and SCLC to chemotherapies (cisplatin, paclitaxel), targeted therapy (olaparib), and radiation. Furthermore, we present the novel finding that BUB1 inhibition sensitized both NSCLC and SCLC to radiotherapy and chemoradiation. Our results demonstrate BUB1 inhibition as a promising strategy to sensitize lung cancers to radiation and chemoradiation therapies.

Background: The combination of the checkpoint inhibitor (CPI) pembrolizumab and platinum-based chemotherapy is effective frontline therapy for advanced non-small cell lung cancer (NSCLC) lacking targetable mutations. Indoleamine 2,3- dioxygenase 1 (IDO1), an enzyme involved in kynurenine production, inhibits immune responses. Inhibition of IDO1 may restore antitumor immunity and augment CPI activity. This trial evaluated addition of epacadostat, a potent and highly selective IDO1 inhibitor, to pembrolizumab and chemotherapy for metastatic NSCLC., Methods: ECHO-306/KEYNOTE-715 was a partial double-blind, randomized phase II study of adults with treatment-naïve stage IV NSCLC not indicated for EGFR-, ALK-, or ROS1-directed therapy. Patients were randomized to one of three treatment arms: epacadostat-pembrolizumab-chemotherapy (E + P + C; blinded), epacadostat-pembrolizumab (E + P; open-label) or placebo-pembrolizumab-chemotherapy (PBO + P + C; blinded). Stratification was by PD-L1 tumor proportion score (< 50% vs. ≥ 50%) and tumor histology (non-squamous vs. squamous). A protocol amendment closed enrollment in the open-label E + P group, excluding it from efficacy analyses. Intravenous pembrolizumab (200 mg) was administered every 21 days and epacadostat 100 mg or matching placebo (oral) twice daily (BID) for ≤ 35 3-week cycles. The primary objective was objective response rate (ORR) for E + P + C vs. PBO + P + C., Results: 178 patients were randomized to E + P + C (n = 91) or PBO + P + C (n = 87); 55 were enrolled in the E + P group. The E + P + C group had a lower confirmed ORR (26.4%; 95% CI 17.7-36.7) than the PBO + P + C group (44.8%; 95% CI 34.1-55.9), with a difference of - 18.5% (95% CI - 32.0 - (- 4.3); one-sided P = 0.9948). The E + P + C group had a numerically higher percentage of confirmed responders with extended response ≥ 6 months (29.2% vs. 15.4%). Circulating kynurenine levels at C1D1 were similar to those at C2D1 in all treatment groups and were not reduced to normal levels with epacadostat 100 mg BID plus P + C. The safety profile of E + P + C was consistent with that for PBO + P + C., Conclusions: Addition of epacadostat 100 mg BID to pembrolizumab and platinum-based chemotherapy was generally well tolerated but did not improve ORR in patients with treatment-naïve metastatic NSCLC. Evaluating epacadostat doses that normalize circulating kynurenine in combination with CPIs may help determine the clinical potential of this combination., Trial Registration: NCT03322566. Registered October 26, 2017., (© 2023. The Author(s).)

Background: Lung cancer is a major public health concern, with high incidence and mortality. Despite advances in targeted therapy and immunotherapy, microtubule stabilizers (paclitaxel, docetaxel), DNA intercalating platinum drugs (cisplatin) and radiation therapy continue to play a critical role in the management of locally advanced and metastatic lung cancer. Novel molecular targets would provide opportunities for improving the efficacies of radiotherapy and chemotherapy., Hypothesis: We hypothesize that BUB1 (Ser/Thr kinase) is over-expressed in lung cancers and that its inhibition will sensitize lung cancers to chemoradiation., Methods: BUB1 inhibitor (BAY1816032) was combined with platinum (cisplatin), microtubule poison (paclitaxel), a PARP inhibitor (olaparib) and radiation in cell proliferation and radiation sensitization assays. Biochemical and molecular assays were used to evaluate their impact on DNA damage signaling and cell death mechanisms., Results: BUB1 expression assessed by immunostaining of lung tumor microarrays (TMAs) confirmed higher BUB1 expression in NSCLC and SCLC compared to that of normal tissues. BUB1 overexpression in lung cancer tissues correlated directly with expression of TP53 mutations in non-small cell lung cancer (NSCLC). Elevated BUB1 levels correlated with poorer overall survival in NSCLC and small cell lung cancer (SCLC) patients. A BUB1 inhibitor (BAY1816032) synergistically sensitized lung cancer cell lines to paclitaxel and olaparib. Additionally, BAY1816032 enhanced cell killing by radiation in both NSCLC and SCLC. Molecular changes following BUB1 inhibition suggest a shift towards pro-apoptotic and anti-proliferative states, indicated by altered expression of BAX, BCL2, PCNA, and Caspases 9 and 3., Conclusion: A direct correlation between BUB1 protein expression and overall survival was shown. BUB1 inhibition sensitized both NSCLC and SCLC to various chemotherapies (cisplatin, paclitaxel) and targeted therapy (PARPi). Furthermore, we present the novel finding that BUB1 inhibition sensitized both NSCLC and SCLC to radiotherapy and chemoradiation. Our results demonstrate BUB1 inhibition as a promising strategy to sensitize lung cancers to radiation and chemoradiation therapies.

Purpose: To provide evidence-based recommendations for patients with stage IV non-small cell lung cancer with driver alterations., Methods: This ASCO living guideline offers continually updated recommendations based on an ongoing systematic review of randomized clinical trials (RCTs), with the latest time frame spanning February to October 2023. An Expert Panel of medical oncology, pulmonary, community oncology, research methodology, and advocacy experts were convened. The literature search included systematic reviews, meta-analyses, and randomized controlled trials. Outcomes of interest include efficacy and safety. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations., Results: This guideline consolidates all previous updates and reflects the body of evidence informing this guideline topic. Eight new RCTs were identified in the latest search of the literature to date., Recommendations: Evidence-based recommendations were updated to address first, second, and subsequent treatment options for patients based on targetable driver alterations.Additional information is available at www.asco.org/living-guidelines.

There are few reported cases of ALK gene rearranged (ALK+) non-small cell lung cancer (NSCLC) during pregnancy. There is a lack of information on the safety of ALK inhibitors in pregnant patients. We present a 25-year-old African American woman who was diagnosed with metastatic ALK+ lung adenocarcinoma at 15 weeks of gestation. Treatment with alectinib was initiated at 18 weeks' gestation with resultant radiological treatment response. The patient did not experience any adverse effects from alectinib during her pregnancy. An elective induction of labor at 39 weeks resulted in an uncomplicated vaginal delivery. This case adds to available data and provides insight on the safety of using alectinib in a pregnant, ALK+ NSCLC patient, allowing the patient to continue her pregnancy to term while treating advanced lung adenocarcinoma., Competing Interests: Disclosures Dr. Luis Gonzalez-Mosquera, MS. Alexandra Rogers, Dr. Nicolina Simth, Dr. Gregory Goyert report no conflict of interest; Dr. Fawzi Abu Rous reports grants from ASCO Conquer Cancer Young Investigator Award. Reports payment or honoraria by MJH Life sciences and Intrinsiq Specialty Solutions. Reports unpaid consultancy role in Genentech. Dr. Shirish Gadgeel reports consulting fees by Astra-Zeneca, Takeda, Genenteci/Roche, Bayer, GSK, Merck, Arcus, Blueprint, Novartis, BMS, Lilly, Daichii, Janssen, Mirati. Reports support for attending meetings from Mirati. Reports participation on Data Safety Monitoring Board or Advisory Board in Astra-Zeneca., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Postimmunotherapy (IO) treatment options for stage IV non-small-cell lung cancer (NSCLC) remain limited. Docetaxel alone or in combination with ramucirumab remains a standard of care, but response rates and survival benefit are suboptimal. Cullin-RING ligases (CRL) catalyze degradation of tumor suppressor proteins and are overactivated in NSCLC. Neddylation, which is catalyzed by the NEDD8 activating enzyme (NAE), is required for the activation of CRLs. Pevonedistat, a first-in-class small molecule NAE inhibitor, exerted antitumor activity when combined with docetaxel in preclinical studies., Methods: We conducted a phase II, single-arm, investigator-initiated study evaluating the efficacy of pevonedistat plus docetaxel in patients with relapsed/refractory stage IV NSCLC. Patients received docetaxel 75 mg/m 2 on day 1 and pevonedistat 25 mg/m 2 on days 1, 3 and 5 of a 21-day cycle. The primary endpoint was objective response rate (ORR)., Results: From March 5, 2018 to January 26, 2021, we enrolled 31 patients. The ORR was 22% (1 CR, 5 PR), median PFS was 4.1 months, and median OS was 13.2 months. The incidence of Grade ≥3 adverse events (AE) was 53% in patients (n = 30) who received at least 1 dose of both drugs, with the most frequent being neutropenia and AST/ALT elevation. One patient was taken off study for a Grade 4 transaminase elevation. There were no Grade 5 toxicities., Conclusion: Our data suggest that the combination of docetaxel and pevonedistat is safe and exerts activity in patients with relapsed NSCLC. These encouraging results suggest that the neddylation pathway is an antitumor pathway that should be further studied., Competing Interests: Disclosure The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Central nervous system (CNS) metastases are frequently diagnosed in patients with non-small cell lung cancer (NSCLC). Only recently, clinical trials are broadening eligibility to include patients with brain metastases, offering the potential for some assessment of CNS efficacy to be made. In this work we aim to review the available information on the activity of small molecule targeted drugs for advanced NSCLC with respect to CNS metastases. We analyze a framework for evaluation assessment regarding trials of systemic agents being conducted in patients with, or at risk from, CNS metastases, and provide examples of NSCLC targeted therapies evaluated in the CNS., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: African American individuals are disproportionately affected by lung cancer in terms of incidence and mortality. In oncogene-driven non-small-cell lung cancer (NSCLC), emerging evidence indicates that underlying molecular heterogeneity, which can be affected by ancestry, contributes to variable drug sensitivity and therapeutic responses. The purpose of this study was to evaluate race-associated differences in reported treatment decisions, therapeutic outcomes, and molecular features in KRAS- and EGFR -mutant NSCLC., Materials and Methods: This is a retrospective study using real-world clinical-genomic data from health systems in the United States to evaluate race-associated outcomes in advanced-stage KRAS - or EGFR -driven NSCLC. Our overall objectives were to evaluate race-associated therapeutic outcomes and to describe molecular features in non-Hispanic Black (NHB) and non-Hispanic White (NHW) patients with NSCLC., Results: A total of 723 NSCLC patients with KRAS and 315 patients with EGFR oncogenic mutations were evaluated. In KRAS -mutant patients, variable outcomes were observed in NHB and NHW patients on the basis of receiving chemotherapy alone or in combination with immune checkpoint inhibitors. NHB patients received treatment at significantly lower rates compared with NHW patients. In the EGFR -mutant cohort, NHB and NHW patients received EGFR-targeted agents at similar rates, and overall survival was not significantly different. Race-associated differences in molecular features included a higher frequency of TP53 comutation in KRAS -mutant NHB patients and higher prevalence of EGFR G719S subtype in NHB patients., Conclusion: In a real-world cohort of patients with NSCLC, we identified race-associated differences in therapeutic outcomes and described molecular characteristics in NHB and NHW patients with NSCLC. To proactively identify patients most likely to respond to systemic therapies, a more comprehensive approach is needed to help guide therapy selection in individualized patient populations.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible patients with previously untreated metastatic nonsquamous non-small-cell lung cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations.

FDA-approved enzalutamide is commonly prescribed to reduce the growth of advanced prostate cancer by blocking androgen receptor function. However, enzalutamide-resistant prostate cancer (ERPC) invariably develops and progresses to metastatic, lethal disease. Management of ERPC poses a special problem not only because available therapeutic regimens cannot effectively kill ERPC cells but also due to their propensity to invade large bones. Moreover, molecular mechanism(s) behind enzalutamide resistance is not properly understood, which is delaying development of newer agents. We found that the pseudokinase, Tribbles 2 (TRIB2), is overexpressed in ERPC cells and plays a critical role in their survival. Forced overexpression of TRIB2 enhances prostate cancer cell growth and confers resistance to physiologic doses of enzalutamide, suggesting that TRIB2 plays an important role in the development and progression of ERPC. Though TRIB2 has emerged as an excellent molecular target for ERPC, suitable inhibitors are not commercially available for effective targeting. By designing a luciferase-tagged TRIB2 fusion protein-based assay system, we screened a library of about 1,600 compounds and found that daclatasvir (DCV), an antiviral drug, effectively inhibits TRIB2-luciferase. We also found that DCV degrades TRIB2 proteins by direct binding and resensitizes ERPC cells to enzalutamide treatment. Moreover, DCV at lower, sublethal doses synergizes with enzalutamide to decrease the viability and induce apoptosis in prostate cancer cells. Because DCV is already approved by the FDA and well tolerated in humans, based on our findings, it appears that DCV is a promising new agent for development of an effective therapy for advanced, enzalutamide-resistant, lethal prostate cancer., (©2023 American Association for Cancer Research.)

Introduction: Amplification of 3q is the most common genetic alteration identified in squamous cell carcinoma of the lung (LUSC), with the most frequent amplified region being 3q26 to 3q28., Methods: In this analysis, we aim to describe the prognostic relevance of 3q amplification by focusing on a minimal common region (MCR) of amplification constituted of 25 genes. We analyzed 511 cases of LUSC from The Cancer Genome Atlas and included 476 in the final analysis., Results: We identified a 25-gene MCR that was amplified in 221 (44.3%) cases and was associated with better disease-specific survival (not reported [NR] versus 9.25 y, 95% confidence interval [CI]: 5.24-NR, log-rank p  = 0.011) and a progression-free interval of 8 years (95% CI: 5.1-NR) versus 4.9 years (95% CI: 3.5-NR, log-rank p  = 0.020). Multivariable analysis revealed that MCR amplification was associated with improved disease-specific survival and progression-free interval., Conclusions: Amplification of the 25-gene MCR within 3q was present in 44% of this cohort, consisting mainly of Caucasian patients with early stage LUSC. This analysis strongly indicates the prognostic relevance of the 25-gene MCR within 3q. We are further evaluating its prognostic and predictive relevance in a racially diverse patient population with advanced LUSC., (© 2023 The Authors.)

Purpose: As screening chest computed tomography for patients at high risk for cancer has become more widely accepted, increasing numbers of patients with early-stage small cell lung cancer (SCLC) are being diagnosed. Although surgery is an accepted option for patients with early-stage SCLC, for patients who decline or cannot undergo surgery, stereotactic body radiation treatment (SBRT) is an alternative. Although prophylactic cranial irradiation (PCI) improves survival in patients with limited-stage SCLC, PCI for early-stage SCLC (stage T1-T2) has not been explored. This study defines survival and recurrence patterns in patients with early-stage SCLC who were treated with surgery or SBRT in the absence of PCI., Methods and Materials: In this single-institution retrospective study, 14 patients diagnosed with early-stage SCLC (stage T1-T2) between July 2015 and May 2021 at a single tertiary care hospital were treated with SBRT or surgery with no PCI. Primary outcomes were locoregional cancer recurrence, distant recurrence, recurrence-free survival, and overall survival. The secondary outcome was development of brain metastasis. Analyses included Cox regression, Kaplan-Meier survival, and log-rank tests., Results: A total of 14 patients (5 women and 9 men) were included in the study: 9 with stage T1 and 5 with stage T2 SCLC. Six patients (43%) received SBRT and 8 (57%) had surgical treatment. All patients except 1 received adjuvant chemotherapy. Median follow-up was 14.3 months (range, 2.4-64.4 months), and the median age at diagnosis was 71.5 years (range, 54-81 years). Cox regression and log-rank tests showed no significant differences in any outcomes between the surgery and SBRT groups, and no patients developed brain metastases during the study period., Conclusions: Data are lacking regarding the benefit of PCI in early-stage SCLC. Although the sample size in this study was too small to draw any conclusions, the findings add to the ongoing dialogue regarding the importance of PCI in this patient population. No difference was identified in survival and cancer recurrence in patients who received either surgery or SBRT in the absence of PCI., (© 2023 The Authors.)

Over the last decade, the use of targeted therapies and immune therapies led to drastic changes in the management lung cancer and translated to improved survival outcomes. This growing arsenal of therapies available for the management of non-small cell lung cancer added more complexity to treatment decisions. The genomic profiling of tumors and the molecular characterization of the tumor microenvironment gradually became essential steps in exploring and identifying markers that can enhance patient selection to facilitate treatment personalization and narrow down therapy options. The advent of innovative diagnostic platforms, such as next-generation sequencing and plasma genotyping (also known as liquid biopsies), has aided in this quest. Currently, programmed cell death ligand 1 expression remains the most recognized and fully validated predictive biomarker of response to immune checkpoint inhibitors. Other markers such as tumor mutational burden, tumor infiltrating lymphocytes, driver mutations, and other molecular elements of the tumor microenvironment bear the potential to be predictive tools; however, the majority are still investigational. In this review, we describe the advances noted thus far on currently validated as well as novel emerging biomarkers that have the potential to guide the use of immunotherapy agents in the management of non-small cell lung cancer., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: We evaluated tissue tumor mutational burden (tTMB) and mutations in STK11, KEAP1, and KRAS as biomarkers for outcomes with pembrolizumab plus platinum-based chemotherapy (pembrolizumab-combination) for NSCLC among patients in the phase 3 KEYNOTE-189 (ClinicalTrials.gov, NCT02578680; nonsquamous) and KEYNOTE-407 (ClinicalTrials.gov, NCT02775435; squamous) trials., Methods: This retrospective exploratory analysis evaluated prevalence of high tTMB and STK11, KEAP1 , and KRAS mutations in patients enrolled in KEYNOTE-189 and KEYNOTE-407 and the relationship between these potential biomarkers and clinical outcomes. tTMB and STK11 , KEAP1 , and KRAS mutation status was assessed using whole-exome sequencing in patients with available tumor and matched normal DNA. The clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mutations/exome., Results: Among patients with evaluable data from whole-exome sequencing for evaluation of tTMB (KEYNOTE-189, n  = 293; KEYNOTE-407, n  = 312) and matched normal DNA, no association was found between continuous tTMB score and overall survival (OS) or progression-free survival for pembrolizumab-combination (Wald test, one-sided p > 0.05) or placebo-combination (Wald test, two-sided p > 0.05) in patients with squamous or nonsquamous histology. Pembrolizumab-combination improved outcomes for patients with tTMB greater than or equal to 175 compared with tTMB less than 175 mutations/exome in KEYNOTE-189 (OS, hazard ratio = 0.64 [95% confidence interval (CI): 0.38‒1.07] and 0.64 [95% CI: 0.42‒0.97], respectively) and KEYNOTE-407 (OS, hazard ratio = 0.74 [95% CI: 0.50‒1.08 and 0.86 [95% CI: 0.57‒1.28], respectively) versus placebo-combination. Treatment outcomes were similar regardless of KEAP1 , STK11, or KRAS mutation status., Conclusions: These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB, STK11, KEAP1, or KRAS mutation status as a biomarker for this regimen., (© 2022 The Authors.)

Introduction: The aim of this study was to evaluate the efficacy of pemetrexed and platinum plus pembrolizumab by baseline tumor burden., Methods: A total of 616 patients in the intention-to-treat population of the KEYNOTE-189 study were included in this analysis. Baseline tumor burden subgroups were identified on the basis of extent of distant metastasis (M1a versus M1b), median number (≤3 versus >3) of organ systems with lesions, or symptom severity score of patient-reported lung cancer-associated symptoms (≤median versus >median). Overall survival (OS), progression-free survival (PFS), and PFS-2 were evaluated by Kaplan-Meier and univariate Cox methods. Objective response rate was analyzed using logistic regression models, and duration of response was analyzed descriptively. Efficacy outcomes were also analyzed according to the programmed death-ligand 1 expression levels., Results: OS and PFS were significantly improved with pemetrexed and platinum plus pembrolizumab in all baseline tumor burden subgroups (M1a stage: OS hazard ratio [HR] = 0.54, p  = 0.0037; PFS HR = 0.48, p  = 0.0001; M1b stage: OS HR = 0.58, p ≤ 0.0001; PFS HR = 0.51, p ≤ 0.0001; number of organ systems with lesion ≤ 3: OS HR = 0.49, p ≤ 0.0001 PFS HR = 0.41, p ≤ 0.0001; >3: OS HR = 0.67, p  = 0.0068; PFS HR = 0.59, p  = 0.0001; symptom severity score ≤ median: HR = 0.51, p ≤ 0.0001; PFS HR 0.49, p ≤ 0.0001; > median: OS HR = 0.60, p  = 0.0003; PFS HR = 0.48, p ≤ 0.0001). PFS2 and objective response rate were also improved with pemetrexed and platinum plus pembrolizumab in all baseline tumor burden subgroups. Efficacy outcomes were generally consistent regardless of programmed death-ligand 1 expression levels., Conclusions: Pemetrexed and platinum plus pembrolizumab were found to have relevant efficacy regardless of the extent of baseline tumor burden and the variables used to define it. These results further support pemetrexed and platinum plus pembrolizumab as the standard of care in the first-line treatment of metastatic nonsquamous NSCLC., (© 2022 Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer.)

Introduction: Lung cancer screening criteria should select candidates with minimal cardiopulmonary comorbidities who are fit for curative lung cancer resection., Methods: We retrospectively analyzed 728 patients with lung cancer for screening eligibility using the U.S. Preventive Services Task Force (USPSTF) 2013 criteria (n = 370). If ineligible for screening, they were further assessed for eligibility using the USPSTF 2021 (n = 121) and National Comprehensive Cancer Network group 2 (NCCN gp 2) (n = 155). Comparisons of cardiopulmonary comorbidities between patients selected by the different lung cancer screening criteria were performed. Excluding missing data, a similar comparison was done between USPSTF 2013 (n = 283) and PLCOm2012 (risk threshold ≥1.51%) (n = 118)., Results: Patients eligible for USPSTF 2021 and NCCN gp 2 had lower rates of airflow obstruction (forced expiratory volume in 1 s [FEV1]/forced vital capacity <0.7) compared with those in USPSTF 2013 (55.4% and 56.8% versus 70.5%). Both USPSTF 2021 and NCCN gp 2 groups had less severe airflow obstruction; only 11.6% and 12.9% of patients, respectively, had percent-predicted FEV1 less than 50% versus 20.3% in the USPSTF 2013 group. Comparing USPSTF 2013 and PLCOm2012 revealed no significant differences in age or the rate of airflow obstruction ( p = 0.06 and p = 0.09 respectively). Nevertheless, rates of percent-predicted FEV1 less than 50% and diffusing capacity of the lungs for carbon monoxide less than 50% were lower in the PLCOm2012 group compared with those in the USPSTF 2013 group (22.3% versus 10.2% and 32.6% versus 20.0%), respectively., Conclusions: The USPSTF 2021 qualifies an additional group of screening candidates who are healthier with better lung reserve, translating to better surgical candidacy but potentially more overdiagnosis. The PLCOm2012, with its better accuracy in selecting patients at risk of cancer, selects an older group with chronic obstructive pulmonary disease but with good lung reserve and potentially less overdiagnosis., (© 2022 The Authors.)

Introduction: Alectinib is a preferred first-line treatment option for advanced ALK -positive NSCLC. Combination regimens of alectinib with immune checkpoint inhibitors are being evaluated for synergistic effects., Methods: Adults with treatment-naive, stage IIIB/IV, or recurrent ALK -positive NSCLC were enrolled into a two-stage phase 1b study. Patients received alectinib 600 mg (twice daily during cycle 1 and throughout each 21-d cycle thereafter) plus atezolizumab 1200 mg (d8 of cycle 1 and then d1 of each 21-d cycle). Primary objectives were to evaluate safety and tolerability of alectinib plus atezolizumab. Secondary objectives included assessments of antitumor activity., Results: In total, 21 patients received more than or equal to 1 dose of alectinib or atezolizumab. As no dose-limiting toxicities were observed in stage 1 (n = 7), the starting dose and schedule were continued into stage 2 (n = 14). Median duration of follow-up was 29 months (range: 1-39). Grade 3 treatment-related adverse events occurred in 57% of the patients, most often rash (19%). No grade 4 or 5 treatment-related adverse events were reported. Confirmed objective response rate was 86% (18 of 21; 95% confidence interval [CI]: 64-97). Median progression-free survival was not estimable (NE) (95% CI: 13 mo-NE), neither was median overall survival (95% CI: 33 mo-NE)., Conclusions: The combination of alectinib and atezolizumab is feasible, but increased toxicity was found compared with the individual agents. With small sample sizes and relatively short follow-up, definitive conclusions regarding antitumor activity cannot be made., (© 2022 The Authors.)

Importance: In 2021, the US Preventive Services Task Force (USPSTF) broadened its age and smoking pack-year requirement for lung cancer screening., Objectives: To compare the 2021 USPSTF lung cancer screening criteria with other lung cancer screening criteria and evaluate whether the sensitivity and specificity of these criteria differ by race., Design, Setting, and Participants: This study included 912 patients with lung cancer and 1457 controls without lung cancer enrolled in an epidemiology study (INHALE [Inflammation, Health, Ancestry, and Lung Epidemiology]) in the Detroit metropolitan area between May 15, 2012, and March 31, 2018. Patients with lung cancer and controls were 21 to 89 years of age; patients with lung cancer who were never smokers and controls who were never smokers were not included in these analyses. Statistical analysis was performed from August 31, 2020, to April 13, 2021., Main Outcomes and Measures: The study assessed whether patients with lung cancer and controls would have qualified for lung cancer screening using the 2013 USPSTF, 2021 USPSTF, and 2012 modification of the model from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCOm2012) screening criteria. Sensitivity was defined as the percentage of patients with lung cancer who qualified for screening, while specificity was defined as the percentage of controls who did not qualify for lung cancer screening., Results: Participants included 912 patients with a lung cancer diagnosis (493 women [54%]; mean [SD] age, 63.7 [9.5] years) and 1457 control participants without lung cancer at enrollment (795 women [55%]; mean [SD] age, 60.4 [9.6] years). With the use of 2021 USPSTF criteria, 590 patients with lung cancer (65%) were eligible for screening compared with 619 patients (68%) per the PLCOm2012 criteria and 445 patients (49%) per the 2013 USPSTF criteria. With the use of 2013 USPSTF criteria, significantly more White patients than African American patients with lung cancer (324 of 625 [52%] vs 121 of 287 [42%]) would have been eligible for screening. This racial disparity was absent when using 2021 USPSTF criteria (408 of 625 [65%] White patients vs 182 of 287 [63%] African American patients) and PLCOm2012 criteria (427 of 625 [68%] White patients vs 192 of 287 [67%] African American patients). The 2013 USPSTF criteria excluded 950 control participants (65%), while the PLCOm2012 criteria excluded 843 control participants (58%), and the 2021 USPSTF criteria excluded 709 control participants (49%). The 2013 USPSTF criteria excluded fewer White control participants than African American control participants (514 of 838 [61%] vs 436 of 619 [70%]). This racial disparity is again absent when using 2021 USPSTF criteria (401 of 838 [48%] White patients vs 308 of 619 [50%] African American patients) and PLCOm2012 guidelines (475 of 838 [57%] White patients vs 368 of 619 [60%] African American patients)., Conclusions and Relevance: This study suggests that the USPSTF 2021 guideline changes improve on earlier, fixed screening criteria for lung cancer, broadening eligibility and reducing the racial disparity in access to screening.

Background: Oncogenic drivers in solid tumors include aberrant activation of mesenchymal epithelial transition factor (MET) and AXL., Objective: This study investigated the safety and antitumor activity of glesatinib, a multitargeted receptor tyrosine kinase inhibitor that inhibits MET and AXL at clinically relevant doses, in combination with erlotinib or docetaxel., Patients and Methods: The phase I portion of this open-label, multicenter study included two parallel arms in which ascending doses of oral glesatinib (starting dose 96 mg/m 2 ) were administered with erlotinib or docetaxel (starting doses 100 mg once daily and 50 mg/m 2 , respectively) using a modified 3 + 3 design. Maximum tolerated dose (MTD) was based on dose-limiting toxicities (DLTs) during the first 21-day treatment cycle. Enrollment focused on patients with solid tumor types typically associated with MET aberration and/or AXL overexpression. The primary objective was to determine the safety profile of the treatment combinations. Antitumor activity and pharmacokinetics (PK) were also assessed., Results: Ten dose levels of glesatinib across three glycolate formulations (unmicronized, micronized, or micronized version 2 [V2] tablets) available during the course of the study were investigated in 14 dose-escalation cohorts (n = 126). MTDs of unmicronized glesatinib plus erlotinib or docetaxel, and micronized glesatinib plus erlotinib were not reached. Micronized glesatinib 96 mg/m 2 plus docetaxel exceeded the MTD. Further dosing focused on glesatinib micronized V2: maximum administered dose (MAD) was 700 mg twice daily with erlotinib 150 mg once daily or docetaxel 75 mg/m 2 every 3 weeks. DLTs, acceptable at lower glesatinib (micronized V2) dose levels, occurred in two of five and two of six patients at the MADs of glesatinib + erlotinib and glesatinib + docetaxel, respectively. Across all cohorts, the most frequent treatment-related adverse events were diarrhea (glesatinib + erlotinib: 84.1%; glesatinib + docetaxel: 45.6%), fatigue (46.4%, 70.4%), and nausea (30.4%, 35.1%). The objective response rate was 1.8% and 12.0% in all glesatinib + erlotinib and glesatinib + docetaxel cohorts, respectively., Conclusions: The safety profile of glesatinib plus erlotinib or docetaxel was acceptable and there were no PK interactions. MADs of glesatinib 700 mg twice daily (micronized V2) with erlotinib 150 mg once daily or docetaxel 75 mg/m 2 every 3 weeks exceeded the MTD by a small margin. Modest signals of efficacy were observed with these treatment combinations in non-genetically selected patients with advanced solid tumors., Clinical Trials Registration: ClinicalTrials.gov NCT00975767; 11 September 2009., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Human epidermal growth factor receptor 2 (ERBB2) mutation is a known oncogenic driver mutation in a small proportion of non-small cell lung cancers (NSCLCs). Many targeted therapies are being developed and investigated for the treatment of ERBB2-mutated NSCLC, however none of these agents have yet been approved as a front-line treatment. Thus, platinum-based chemotherapy with or without immunotherapy remains the preferred first-line therapy for ERBB2-mutated NSCLC., Objective: We aimed to study the activity of chemotherapy in combination with pembrolizumab as first-line treatment in patients with stage IV ERBB2-mutated NSCLC., Patients and Methods: We retrospectively identified five patients with ERBB2-mutated NSCLC treated with carboplatin, pemetrexed and pembrolizumab as first-line therapy between 2018 and 2020. Overall survival (OS), progression-free survival (PFS), and time to next therapy (TTNT) were summarized by Kaplan-Meier methodology using R 4.0.5 with median time to event. Response rates defined by partial response (PR) or PR + stable disease (SD) and 95% Clopper-Pearson confidence interval (CI) were calculated., Results: The median age of these five patients was 60 years and all five patients' tumors had ERBB2 mutations-4 had exon 20 mutation and 1 had exon 23 mutation. With a median follow-up of 32 months, the median OS was 24 months, the median PFS was 9 months, and the median TTNT was 9 months. The response rate was 0.6 for PR (Clopper-Pearson exact 95% CI 0.147-0.947) and 0.8 for PR and SD (Clopper-Pearson exact 95% CI 0.284-0.995). No unexpected toxicities were observed., Conclusion: In a small number of patients, chemotherapy and pembrolizumab as first-line therapy in ERBB2-mutated NSCLC patients demonstrated activity similar to previous reports with this regimen. Future clinical trials are needed to determine the role of chemotherapy and immunotherapy for this patient population in the context of emerging targeted agents., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)