E-Cigarette Use and Lung Cancer Screening Uptake.

This cross-sectional study examines e-cigarette use and lung cancer screening uptake among individuals in the US.

Outcomes of initial therapy for synchronous brain metastases from small cell lung cancer: a single-institution retrospective analysis.

Small cell lung cancer (SCLC) has a propensity for brain metastases, which is associated with poor prognosis. We sought to determine predictors of overall survival (OS) and brain progression-free survival (bPFS) in SCLC patients with synchronous brain metastases at the time of initial SCLC diagnosis. A total of 107 SCLC patients with synchronous brain metastases treated at a single institution were included in this retrospective analysis. These patients had brain lesions present on initial staging imaging. Survival was estimated using the Kaplan-Meier method with log-rank test. Factors predictive of OS and bPFS were analyzed using Cox proportional hazards regression model. Median OS for the entire cohort was 9 months (interquartile range, 4.2-13.8 months) and median bPFS was 7.3 months (interquartile range, 3.5-11.1 months). OS was 30.3% at 1 year and 14.4% at 2 years, while bPFS was 22.0% at 1 year and 6.9% at 2 years. The median number of brain lesions at diagnosis was 3 (interquartile range, 2-8), and the median size of the largest metastasis was 2.0 cm (interquartile range, 1.0-3.3 cm). Increased number of brain lesions was significantly associated with decreased OS. Patients who received both chemotherapy and whole brain radiation therapy (WBRT) had improved OS (P=0.02) and bPFS (P=0.005) compared to those who had either chemotherapy or WBRT alone. There was no significant difference in OS or bPFS depending on the sequence of therapy or the dose of WBRT. Thirteen patients underwent upfront brain metastasis resection, which was associated with improved OS (P=0.02) but not bPFS (P=0.09) compared to those who did not have surgery. The combination of chemotherapy and WBRT was associated with improved OS and bPFS compared to either modality alone. Upfront brain metastasis resection was associated with improved OS but not bPFS compared to those who did not have surgery.

RESILIENT Part 2: A Randomized, Open-Label Phase III Study of Liposomal Irinotecan Versus Topotecan in Adults With Relapsed Small Cell Lung Cancer.

PURPOSE: The phase III RESILIENT trial compared second-line liposomal irinotecan with topotecan in patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: Patients with SCLC and progression on or after first-line platinum-based chemotherapy were randomly assigned (1:1) to intravenous (IV) liposomal irinotecan (70 mg/m2 every 2 weeks in a 6-week cycle) or IV topotecan (1.5 mg/m2 daily for 5 consecutive days, every 3 weeks in a 6-week cycle). The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) and objective response rate (ORR). RESULTS: Among 461 randomly assigned patients, 229 received liposomal irinotecan and 232 received topotecan. The median follow-up was 18.4 months. The median OS was 7.9 months with liposomal irinotecan versus 8.3 months with topotecan (hazard ratio [HR], 1.11 [95% CI, 0.90 to 1.37]; P = .31). The median PFS per blinded independent central review (BICR) was 4.0 months with liposomal irinotecan and 3.3 months with topotecan (HR, 0.96 [95% CI, 0.77 to 1.20]; nominal P = .71); ORR per BICR was 44.1% (95% CI, 37.6 to 50.8) and 21.6% (16.4 to 27.4), respectively. Overall, 42.0% and 83.4% of patients receiving liposomal irinotecan and topotecan, respectively, experienced grade ≥3 related treatment-emergent adverse events (TEAEs). The most common grade ≥3 related TEAEs were diarrhea (13.7%), neutropenia (8.0%), and decreased neutrophil count (4.4%) with liposomal irinotecan and neutropenia (51.6%), anemia (30.9%), and leukopenia (29.1%) with topotecan. CONCLUSION: Liposomal irinotecan and topotecan demonstrated similar median OS and PFS in patients with relapsed SCLC. Although the primary end point of OS was not met, liposomal irinotecan demonstrated a higher ORR than topotecan. The safety profile of liposomal irinotecan was consistent with its known safety profile; no new safety concerns emerged.

Pharmacokinetic study of capivasertib and the CYP3A4 substrate midazolam in patients with advanced solid tumors.

PURPOSE: Capivasertib, a potent, selective inhibitor of all three AKT serine/threonine kinase (AKT) isoforms, is being evaluated in phase 3 trials in advanced breast and prostate cancer. This study evaluated the drug-drug interaction risk of capivasertib with the cytochrome P450 3A substrate midazolam in previously treated adults with advanced solid tumors. METHODS: Patients received oral capivasertib 400 mg twice daily (BID) on an intermittent schedule (4 days on/3 days off) starting on day 2 of cycle 1 (29 days) and on day 1 of each 28-day cycle thereafter. In cycle 1 only, patients received oral midazolam (1 mg) on day 1 (alone), and days 8 and 12 (3rd day off and 4th day on capivasertib, respectively). Midazolam pharmacokinetics on days 8 and 12 were analyzed versus day 1. Capivasertib, with or without standard-of-care treatment, was continued in patients deemed likely to benefit. Safety and exploratory efficacy analyses were conducted. RESULTS: Capivasertib-midazolam coadministration increased midazolam exposure (n = 21): geometric mean ratio (90% confidence interval) AUCinf and Cmax was 1.13 (0.97-1.32) and 1.15 (0.99-1.33) for day 8 versus day 1, and 1.75 (1.50-2.05) and 1.25 (1.08-1.46) for day 12 versus day 1. The capivasertib safety profile was manageable when administered with or without midazolam. Two patients had partial responses to treatment. CONCLUSION: The up to 1.75-fold increase in midazolam exposure indicates capivasertib is a weak CYP3A inhibitor at 400 mg BID on an intermittent schedule. Capivasertib was well tolerated; exploratory efficacy analysis demonstrated evidence of clinical activity in this heavily pre-treated population. CLINICALTRIALS: gov: NCT04958226.

A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors.

BACKGROUND: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. RESULTS: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56-62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1T1997M mutation. CONCLUSIONS: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations.

A Relative Bioavailability, Bioequivalence, and Food Effect Study of Niraparib Tablets in Patients with Advanced Solid Tumors.

PURPOSE: The poly (ADP-ribose) polymerase inhibitor niraparib is indicated as maintenance treatment in patients with certain subtypes of advanced ovarian cancer, and is being investigated in patients with other solid tumors. Niraparib is available in 100-mg capsules with a starting dosage of 200 or 300 mg/d. This study assessed the relative bioavailability (BA) and bioequivalence (BE) between a 1 × 300-mg tablet relative to 3 × 100-mg niraparib capsules. In addition, the food effect (FE) of a high-fat meal on the pharmacokinetic (PK) properties of tablet-formulated niraparib was investigated. METHODS: This was a US-based, 3-stage, open-label, multicenter, single-crossover, randomized-sequence study. Enrolled patients were 18 years and older, with histologically or cytologically confirmed advanced solid tumors (metastatic or local) and disease progression despite standard therapy. Patients were randomly assigned 1:1 to receive niraparib 1 × 300-mg tablet or 3 × 100-mg capsules in the BA and BE stages or 1 × 300-mg tablet in a fasted or fed (high-fat meal) state in the FE stage. Across all study stages, PK parameters were assessed for 7 days after each dose (tablet or capsule) or prandial state (fasted or fed). In the BA stage, patients crossed over to the other treatment after a 7-day washout period, which was extended to 14 days in the BE and FE stages. Tolerability was assessed for patients who received any amount of niraparib. FINDINGS: The BA-, BE-, and FE-evaluable populations comprised 23, 108, and 19 patients, respectively, who completed both treatment periods in each study stage, had sufficient concentration data to accurately estimate PK parameters without niraparib carryover, and did not experience disqualifying events. PK parameters were similar after dosing with tablet or capsule formulations; the 90% CIs of the geometric least square means for Cmax, AUC0-t, and AUC0-∞ were within the 0.80 to 1.25 BE limits. In the FE stage, Cmax, AUC0-t, and AUC0-∞ were 11%, 32%, and 28% higher, respectively, in the fed versus fasted state. The safety population included 29, 168, and 28 patients in the BA, BE, and FE stages, respectively, who received niraparib. No new safety signals were identified. IMPLICATIONS: Niraparib tablets were found to be bioequivalent to capsules. A modest (≤32%) FE was observed with a high-fat meal, but was not considered to be clinically meaningful, given niraparib's PK variability. CLINICALTRIALS: gov identifier: NCT03329001. (Clin Ther. 2024;46:XXX-XXX) © 2024 Elsevier HS Journals, Inc.

Phase II study investigating the efficacy and safety of glesatinib (MGCD265) in patients with advanced NSCLC containing MET activating alterations.

OBJECTIVES: Dysregulated signaling by mesenchymal epithelial transition factor (MET) and heightened AXL activation are implicated in the pathogenesis of non-small cell lung cancer (NSCLC). Glesatinib (MGCD265) is an investigational, oral inhibitor of MET and AXL. MATERIALS AND METHODS: This open-label, Phase II study investigated glesatinib (free-base suspension [FBS] capsule 1050 mg BID or spray-dried dispersion [SDD] tablet 750 mg BID) in patients with advanced, previously treated NSCLC across four cohorts grouped according to presence of MET activating mutations or amplification in tumor or ctDNA. The primary endpoint was objective response rate (ORR). RESULTS: Sixty-eight patients were enrolled: n = 28 and n = 8 with MET exon 14 skipping mutations in tumor tissue and ctDNA, respectively, and n = 20 and n = 12 with MET gene amplification in tumor tissue and ctDNA, respectively. Overall, ORR was 11.8 %, median progression-free survival was 4.0 months, and median overall survival was 7.0 months. Among patients with MET activating mutations, ORR was 10.7 % with tumor testing and 25.0 % with ctDNA testing. For MET amplification, responses were observed only in patients enrolled by tumor testing (ORR 15.0 %). Diarrhea (82.4 %), nausea (50.0 %), increased alanine aminotransferase (41.2 %), fatigue (38.2 %), and increased aspartate aminotransferase (36.8 %) were the most frequent adverse events assessed as related to study medication. Glesatinib exposure was similar with the SDD tablet and FBS capsule formulations. The study was terminated early by the sponsor due to modest clinical activity. CONCLUSIONS: Glesatinib had an acceptable safety profile in patients with advanced, pre-treated NSCLC with MET activating alterations. Modest clinical activity was observed, which likely reflects suboptimal drug bioavailability suggested by previously reported Phase I data, and pharmacodynamic findings of lower than anticipated increases in circulating soluble shed MET ectodomain (s-MET).

The Impact of Prophylactic Cranial Irradiation and Consolidative Thoracic Radiation Therapy for Extensive Stage Small-Cell Lung Cancer in the Transition to the Chemo-Immunotherapy Era: A Single Institution Series.

INTRODUCTION: Extensive-stage small-cell lung cancer (ES-SCLC) continues to have poor survival due to its aggressive behavior, despite improvements with incorporation of immunotherapy with standard chemotherapy. Controversy exists regarding the role of consolidative thoracic radiation therapy (TRT) and prophylactic cranial irradiation (PCI) in ES-SCLC due to high recurrence rates. We report our institutional result of the benefit of PCI and TRT in ES-SCLC. METHODS: Patients with ES-SCLC without intracranial metastasis at diagnosis (N = 163) were included. All patients completed systemic therapy with or without immunotherapy based on time of standard of care. Cohorts were divided by systemic therapy use and further subdivided by treatment with PCI and TRT. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method with log-rank test for comparison. The effects of TRT and PCI were estimated by multivariable (MVA) Cox regression. RESULTS: Seventy-four patients (45.4%) received TRT, and 33.1% (n = 54) received PCI. The median follow-up was 11 months (3-85 months). PCI improved median OS to 15 months from 10 months, P = .02) and median PFS to 8.5 months from 5 months (P = .02) which remained significant on MVA, P = .02 and P = .02, respectively. TRT improved OS on UVA (P = 0.002) but was not significant on MVA. TRT did not improve PFS. CONCLUSION: This study including chemotherapy and chemo-immunotherapy suggests improved outcomes with addition of PCI in patients with ES-SCLC while TRT did not show benefit to either OS or PFS. A future trial is needed to evaluate the role of TRT and PCI in the era of chemo-immunotherapy.

Subjective and Objective Hearing Loss Among US Adult Cancer Survivors.

Importance: Cancer survivors are at a higher risk of developing hearing loss (HL) due to older age, chemotherapy, and radiotherapy. However, the prevalence of HL among US cancer survivors remains unknown. Additionally, there is a lack of uniform HL screening guidelines for this enlarging population. Objective: To estimate the prevalence of subjective HL and objective HL by audiometry test among cancer survivors and compare them with the general population as well as to assess the performance of subjective HL questions in detecting true (ie, audiometry-confirmed) HL. Design, Setting, and Participants: In a cross-sectional design, adults between ages 20 and 80 years who had audiometry testing and responded to a hearing questionnaire from the National Health and Nutrition Examination Survey (2011-2012, 2015-2016, and 2017 to March 2020 prepandemic survey cycles) were selected. Data analysis was conducted from August 13, 2022, to July 26, 2023. Main Outcomes and Measures: The weighted prevalence of subjective HL (troublesome hearing and tinnitus) and objective HL (speech-frequency HL and high-frequency HL) by audiometry were calculated. Analyses with χ2 testing and multiadjusted logistic regression models were used to compare HL between cancer survivors and the general population. To evaluate the performance of subjective HL questions as a tool to screen for objective HL by audiometry, areas under the curve were estimated using age- and gender-adjusted logistic regression. Results: Among the total 9337 participants (weighted n = 90 098 441; 51.2% women), 10.3% were cancer survivors. Compared with the general population, cancer survivors had a higher prevalence of troublesome hearing (adjusted odds ratio [AOR], 1.43; 95% CI, 1.11-1.84), tinnitus (AOR, 1.28; 95% CI, 0.94-1.74), speech-frequency HL (AOR, 1.43; 95% CI, 1.11-1.85), and high-frequency HL (AOR, 1.74; 95% CI, 1.29-2.34). When using the subjective HL tool and questioning regarding whether the participants were having troublesome hearing and/or tinnitus in screening for HL, the age- and gender-adjusted area under the curve was 0.88 in detecting speech-frequency HL and 0.90 in detecting high-frequency HL. Conclusion and Relevance: The findings of this study suggest that cancer survivors have a significantly higher prevalence of HL than the general population. Two subjective HL questions could potentially accurately identify those who have true HL and provide a simple and efficient screening tool for health care professionals. Cancer survivors and their families should be educated and encouraged to discuss hearing concerns, and health care professionals should facilitate raising awareness and provide early screening and timely referral when HL is identified.

Outcomes of Antineoplastic Immunotherapy at a Large Healthcare Organization: Impact of Provider, Race and Socioeconomic Status.

Purpose: Disparities in cancer care delivery remain a pressing health-care crisis within the United States (US). The use of immune checkpoint inhibitors (ICIs) and their management may be a disparity generator that impacts survival. This retrospective study assessed disparities in a cohort of patients with a variety of solid tumors treated with ICIs within a single health-care organization focusing on the impact of race, socioeconomic status (SES) and site of care delivery on survival and the development of severe immune-related adverse events (irAEs). Patients and Methods: Manual chart review was performed on all patients with solid tumors treated with ICIs within a health-care organization from 2012 to 2018. Care delivery was dichotomized as DOP (disease-oriented provider at academic center) and COP (community oncology provider). Primary and secondary outcomes were overall survival (OS) and rates of grade 3-4 irAEs, respectively. Relationships with covariates of interest, including race, socioeconomic status and type of care delivery, were assessed among both outcomes. Results: A total of 1070 eligible patients were identified. Of those, 11.4% were of Black race, 59.7% had either non-small cell lung cancer (NSCLC) or melanoma and 82.8% had stage IV disease. Patients of Black race and lower SES were more likely to be treated by DOPs (p<0.0001). A superior OS was associated with care delivered by DOPs when compared to COPs (HR 0.68; 95% CI 0.56-0.84; p=0.0002), which was durable after accounting for race, SES, histopathologic diagnosis and disease stage. Melanoma patients experienced higher rates of severe irAEs (HR 2.37; 95% CI 1.42-3.97; p=0.001). Race, SES and site of care delivery were not related to rates of severe irAEs. Conclusion: In a large health-care organization, patients treated with checkpoint inhibitors by DOPs benefited from a significant OS advantage that was durable after controlling for racial and socioeconomic factors, providing evidence that disease-oriented care has the potential to mitigate racial and socioeconomic disparities.

Larotrectinib efficacy and safety in adult patients with tropomyosin receptor kinase fusion sarcomas.

BACKGROUND: Larotrectinib, a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor, has demonstrated efficacy in adult and pediatric patients with various solid tumors harboring NTRK gene fusions. This subset analysis focuses on the efficacy and safety of larotrectinib in an expanded cohort of adult patients with TRK fusion sarcomas. METHODS: Patients (≥18 years old) with sarcomas harboring NTRK gene fusions were identified from three clinical trials. Patients received larotrectinib 100 mg orally twice daily. Response was investigator-assessed per RECIST v1.1. Data cutoff was July 20, 2021. RESULTS: At the data cutoff, 36 adult patients with TRK fusion sarcomas had initiated larotrectinib therapy: two (6%) patients had bone sarcomas, four (11%) had gastrointestinal stromal tumors, and 30 (83%) had soft tissue sarcomas. All patients were evaluable for response and demonstrated an objective response rate of 58% (95% confidence interval, 41-74). Patients responded well to larotrectinib regardless of number of prior lines of therapy. Adverse events (AEs) were mostly grade 1/2. Grade 3 treatment-emergent AEs (TEAEs) occurred in 15 (42%) patients. There were no grade 4 TEAEs. Two grade 5 TEAEs were reported, neither of which were considered related to larotrectinib. Four (11%) patients permanently discontinued treatment due to TEAEs. CONCLUSIONS: Larotrectinib demonstrated robust and durable responses, extended survival benefit, and a favorable safety profile in adult patients with TRK fusion sarcomas with longer follow-up. These results continue to demonstrate that testing for NTRK gene fusions should be incorporated into the clinical management of adult patients with various types of sarcomas. PLAIN LANGUAGE SUMMARY: Tropomyosin receptor kinase (TRK) fusion proteins result from translocations involving the NTRK gene and cause cancer in a range of tumor types. Larotrectinib is an agent that specifically targets TRK fusion proteins and is approved for the treatment of patients with TRK fusion cancer. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. Over half of patients had a durable response to larotrectinib, with no unexpected side effects. These results show that larotrectinib is safe and effective in adult patients with TRK fusion sarcomas.

Survival in elderly patients with breast cancer with and without autoimmune disease.

BACKGROUND: Patients with certain autoimmune conditions are at a reduced risk of developing breast cancer compared to the general population. Despite this, little is known about outcomes in patients with breast cancer who have a concurrent autoimmune diagnosis. METHODS: This study compared differences in outcomes between women with breast cancer who had or did not have an autoimmune diagnosis. The SEER-Medicare databases (2007-2014) were used to identify patients with breast cancer and diagnosis codes were used to identify those with an autoimmune disorder. RESULTS: The studied autoimmune diseases had a prevalence of 27% among the 137,324 patients with breast cancer. Autoimmune disease was associated with significantly longer overall survival (OS) and significantly lower cancer-specific mortality (CSM) among stage IV breast cancer patients (p < 0.0001). After controlling for the effects of age, race, chronic kideny disease, chemotherapy, and radiation therapy autoimmune disease was still predictive of improved OS (HR: 1.45, 95% CI: 1.35-1.55, p < 0.0001) and CSM (HR: 1.40, 95% CI: 1.29-1.5, p < 0.0001). By contrast, in patients with stage I-III breast cancer, the presence of an autoimmune diagnosis was associated with a lower OS (p < 0.0001, p < 0.0001, and p = 0.026, respectively), compared to patients without autoimmune disease. CONCLUSIONS: We found a higher prevalence of rheumatoid arthritis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus in patients with breast cancer compared to age matched cohorts in the general population. The presence of an autoimmune diagnosis was associated with a lower OS in stages I-III breast cancer and improved OS and CSM in patients with stage IV disease. These results suggest that anti-tumor immunity plays an important role in late stage breast cancer and could potentially be exploited to improve the effectiveness of immunotherapy.

Integrative Analysis of a Large Real-World Cohort of Small Cell Lung Cancer Identifies Distinct Genetic Subtypes and Insights into Histologic Transformation.

Small cell lung cancer (SCLC) is a recalcitrant neuroendocrine carcinoma with dismal survival outcomes. A major barrier in the field has been the relative paucity of human tumors studied. Here we provide an integrated analysis of 3,600 "real-world" SCLC cases. This large cohort allowed us to identify new recurrent alterations and genetic subtypes, including STK11-mutant tumors (1.7%) and TP53/RB1 wild-type tumors (5.5%), as well as rare cases that were human papillomavirus-positive. In our cohort, gene amplifications on 4q12 are associated with increased overall survival, whereas CCNE1 amplification is associated with decreased overall survival. We also identify more frequent alterations in the PTEN pathway in brain metastases. Finally, profiling cases of SCLC containing oncogenic drivers typically associated with NSCLC demonstrates that SCLC transformation may occur across multiple distinct molecular cohorts of NSCLC. These novel and unsuspected genetic features of SCLC may help personalize treatment approaches for this fatal form of cancer. SIGNIFICANCE: Minimal changes in therapy and survival outcomes have occurred in SCLC for the past four decades. The identification of new genetic subtypes and novel recurrent mutations as well as an improved understanding of the mechanisms of transformation to SCLC from NSCLC may guide the development of personalized therapies for subsets of patients with SCLC. This article is highlighted in the In This Issue feature, p. 1501.

Current and Emerging Treatment Options for Patients With Relapsed Small-cell Lung Carcinoma: A Systematic Literature Review.

Second-line treatment options are limited for patients with small-cell lung cancer (SCLC). We conducted a PRISMA-standard systematic literature review to evaluate the treatment landscape for patients with relapsed SCLC (PROSPERO number: CRD42022299759). Systematic searches of MEDLINE, Embase, and Cochrane Library were performed (October 2022) to identify publications (prior 5 years) from prospective studies of therapies for relapsed SCLC. Publications were screened against predetermined eligibility criteria; data were extracted to standardized fields. Publication quality was assessed using GRADE. The data were analyzed descriptively, grouped by drug class. Overall, 77 publications involving 6349 patients were included. Studies of tyrosine kinase inhibitors (TKIs) with established cancer indications accounted for 24 publications; topoisomerase I inhibitors for 15; checkpoint inhibitors (CPIs) for 11, and alkylating agents for 9 publications. The remaining 18 publications featured chemotherapies, small-molecule inhibitors, investigational TKIs and monoclonal antibodies, and a cancer vaccine. According to GRADE assessment, 69% of the publications reported low-/very-low-quality evidence; quality limitations included lack of randomization and small sample sizes. Only 6 publications/6 trials reported phase 3 data; 5 publications/2 trials reported phase 2/3 results. Overall, the clinical potential of alkylating agents and CPIs remained unclear; investigations of combination approaches and biomarker-directed usage are warranted. Phase 2 data from TKI trials were consistently promising; no phase 3 data were available. Phase 2 data for a liposomal formulation of irinotecan were promising. We confirmed an absence of promising investigational drug/regimens in late-stage development; thus, relapsed SCLC remains an area of high unmet need.

Tarlatamab, a First-in-Class DLL3-Targeted Bispecific T-Cell Engager, in Recurrent Small-Cell Lung Cancer: An Open-Label, Phase I Study.

PURPOSE: Small-cell lung cancer (SCLC) is an aggressive malignancy with limited treatments. Delta-like ligand 3 (DLL3) is aberrantly expressed in most SCLC. Tarlatamab (AMG 757), a bispecific T-cell engager molecule, binds both DLL3 and CD3 leading to T-cellb-mediated tumor lysis. Herein, we report phase I results of tarlatamab in patients with SCLC. PATIENTS AND METHODS: This study evaluated tarlatamab in patients with relapsed/refractory SCLC. The primary end point was safety. Secondary end points included antitumor activity by modified RECIST 1.1, overall survival, and pharmacokinetics. RESULTS: By July 19, 2022, 107 patients received tarlatamab in dose exploration (0.003 to 100 mg; n = 73) and expansion (100 mg; n = 34) cohorts. Median prior lines of anticancer therapy were 2 (range, 1-6); 49.5% received antiprogrammed death-1/programmed death ligand-1 therapy. Any-grade treatment-related adverse events occurred in 97 patients (90.7%) and grade b % 3 in 33 patients (30.8%). One patient (1%) had grade 5 pneumonitis. Cytokine release syndrome was the most common treatment-related adverse event, occurring in 56 patients (52%) including grade 3 in one patient (1%). Maximum tolerated dose was not reached. Objective response rate was 23.4% (95% CI, 15.7 to 32.5) including two complete and 23 partial responses. The median duration of response was 12.3 months (95% CI, 6.6 to 14.9). The disease control rate was 51.4% (95% CI, 41.5 to 61.2). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.1 to 5.4) and 13.2 months (95% CI, 10.5 to not reached), respectively. Exploratory analysis suggests that selecting for increased DLL3 expression can result in increased clinical benefit. CONCLUSION: In patients with heavily pretreated SCLC, tarlatamab demonstrated manageable safety with encouraging response durability. Further evaluation of this promising molecule is ongoing.

Mistletoe lectin inhibits growth of Myc-amplified small-cell lung cancer.

BACKGROUND: Small-cell lung cancer (SCLC) is the deadliest form of lung cancer but lacks targeted therapies. METHODS: We studied the effect of the natural product mistletoe lectin (ML) in pre-clinical models of SCLC, focusing on cell lines with amplification of the myc family oncogenes C-myc and N-myc. RESULTS: We found that ML treatment inhibits growth of SCLC cell lines in culture and induces apoptosis. ML treatment also decreases the expression of the amplified myc proteins. Over-expression of either C-myc or N-myc results in enhanced SCLC cell sensitivity to ML. In a mouse xenograft model of SCLC, treatment with ML results in decreased tumor growth over 4 weeks with evidence of increased apoptosis in tumors from treated animals. CONCLUSION: Overall, our results demonstrate that ML exhibits therapeutic potential in SCLC, that is at least partially dependent on myc protein expression.

Effect of Pevonedistat, an Investigational NEDD8-Activating Enzyme Inhibitor, on the QTc Interval in Patients With Advanced Solid Tumors.

The purpose of this study was to assess the effect of pevonedistat, a neural precursor cell expressed, developmentally down-regulated protein 8 (NEDD8)-activating enzyme inhibitor, on the heart rate-corrected QT (QTc) interval in cancer patients. Patients were randomized 1:1 to receive pevonedistat 25 or 50 mg/m2 on day 1 and the alternate dose on day 8. Triplicate electrocardiograms were collected at intervals over 0-11 hours and at 24 hours via Holter recorders on days -1 (baseline), 1, and 8. Changes from time-matched baseline values were calculated for QTc by Fridericia (QTcF), PR, and QRS intervals. Serial time-matched blood samples for analysis of pevonedistat plasma pharmacokinetics were collected and a concentration-QTc analysis conducted. Safety was assessed by monitoring vital signs, physical examinations, and clinical laboratory tests. Forty-four patients were included in the QTc analysis. Maximum least square (LS) mean increase from time-matched baseline in QTcF was 3.2 milliseconds at 1 hour postdose for pevonedistat at 25 mg/m2 , while the LSs mean change from baseline in QTcF was -1.7 milliseconds 1 hour postdose at 50 mg/m2 . The maximum 2-sided 90% upper confidence bound was 6.7 and 2.9 milliseconds for pevonedistat at 25 and 50 mg/m2 , respectively. Pevonedistat did not result in clinically relevant effects on heart rate, nor on PR or QRS intervals. Results from pevonedistat concentration-QTc analysis were consistent with these findings. Administration of pevonedistat to cancer patients at a dose of up to 50 mg/m2 showed no evidence of QT prolongation, indicative of the lack of clinically meaningful effects on cardiac repolarization. ClinicalTrials.gov identifier: NCT03330106 (first registered on November 6, 2017).

Retinoblastoma Expression and Targeting by CDK4/6 Inhibitors in Small Cell Lung Cancer.

The canonical model of "small cell lung cancer" (SCLC) depicts tumors arising from dual inactivation of TP53 and RB1. However, many genomic studies have persistently identified tumors with no RB1 mutations. Here, we examined RB1 protein expression and function in SCLC. RB1 expression was examined by IHC analysis of 62 human SCLC tumors. These studies showed that ∼14% of SCLC tumors expressed abundant RB1 protein, which is associated with neuroendocrine gene expression and is enriched in YAP1 expression, but no other lineage proteins that stratify SCLC. SCLC cells and xenograft tumors with RB1 protein expression were sensitive to growth inhibition by the CDK4/6 inhibitor palbociclib, and this inhibition was shown to be dependent on RB1 expression by CRISPR knockout. Furthermore, a patient with biopsy-validated wild-type RB1 SCLC who received the CDK4/6 inhibitor abemaciclib demonstrated a dramatic decrease in mutant TP53 ctDNA allelic fraction from 62.1% to 0.4% and decreased tumor mass on CT scans. Importantly, IHC of the diagnostic biopsy specimen showed RB1 positivity. Finally, we identified a transcriptomics-based RB1 loss-of-function signature that discriminates between SCLC cells with or without RB1 protein expression and validated it in the patient who was responsive to abemaciclib, suggesting its potential use to predict CDK4/6 inhibitor response in patients with SCLC. Our study demonstrates that RB1 protein is an actionable target in a subgroup of SCLC, a cancer that exhibits no currently targetable mutations.