Real-world practice patterns and outcomes for RAI-refractory differentiated thyroid cancer.

Background: The optimal timing for initiating multi-kinase inhibitors (MKIs) in patients with radioactive iodine-refractory (RAI-R) differentiated thyroid cancer (DTC) remains unclear. Thus, we evaluated the real-world practice patterns and outcomes in asymptomatic patients with progressive RAI-R DTC (≥1 lesion ≥1 cm in diameter) in the USA (US population) and outside the USA (non-US population). Methods: In this prospective, non-interventional, open-label study, eligible patients were chosen by treating physicians to receive MKI therapy (cohort 1) or undergo active surveillance (cohort 2) at study entry. Cohort 2 patients were allowed to transition to MKI therapy later. The primary endpoint was time to symptomatic progression (TTSP) from study entry. Data were compared descriptively. When endpoints were inestimable, 36-month rates were calculated. Results: Of the 647 patients, 478 underwent active surveillance (cohort 2) and 169 received MKI treatment (cohort 1). Patients underwent surveillance at a higher rate in the US (92.6%) vs the non-US (66.9%) populations. Half of US and non-US patients who qualified for MKI treatment had initial American Thyroid Association (ATA) low-to-intermediate-risk disease. In cohort 2, the 36-month TTSP rates from study entry were 65.6% and 66.5% in the US and non-US populations, respectively. Cohort 2 patients treated later demonstrated 36-month TTSP rates of 30.8% and 55.8% in the US and non-US populations, respectively. Conclusions: Active surveillance is a viable option for asymptomatic patients with progressive RAI-R DTC. However, early intervention with MKI therapy may be more suitable for others. Further research is needed to identify patients who are optimal for active surveillance. Registration: NCT02303444.

Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer.

BACKGROUND: Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 and CD3, showed promising antitumor activity in a phase 1 trial in patients with previously treated small-cell lung cancer. METHODS: In this phase 2 trial, we evaluated the antitumor activity and safety of tarlatamab, administered intravenously every 2 weeks at a dose of 10 mg or 100 mg, in patients with previously treated small-cell lung cancer. The primary end point was objective response (complete or partial response), as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Overall, 220 patients received tarlatamab; patients had previously received a median of two lines of treatment. Among patients evaluated for antitumor activity and survival, the median follow-up was 10.6 months in the 10-mg group and 10.3 months in the 100-mg group. An objective response occurred in 40% (97.5% confidence interval [CI], 29 to 52) of the patients in the 10-mg group and in 32% (97.5% CI, 21 to 44) of those in the 100-mg group. Among patients with an objective response, the duration of response was at least 6 months in 59% (40 of 68 patients). Objective responses at the time of data cutoff were ongoing in 22 of 40 patients (55%) in the 10-mg group and in 16 of 28 patients (57%) in the 100-mg group. The median progression-free survival was 4.9 months (95% CI, 2.9 to 6.7) in the 10-mg group and 3.9 months (95% CI, 2.6 to 4.4) in the 100-mg group; the estimates of overall survival at 9 months were 68% and 66% of patients, respectively. The most common adverse events were cytokine-release syndrome (in 51% of the patients in the 10-mg group and in 61% of those in the 100-mg group), decreased appetite (in 29% and 44%, respectively), and pyrexia (in 35% and 33%). Cytokine-release syndrome occurred primarily during treatment cycle 1, and events in most of the patients were grade 1 or 2 in severity. Grade 3 cytokine-release syndrome occurred less frequently in the 10-mg group (in 1% of the patients) than in the 100-mg group (in 6%). A low percentage of patients (3%) discontinued tarlatamab because of treatment-related adverse events. CONCLUSIONS: Tarlatamab, administered as a 10-mg dose every 2 weeks, showed antitumor activity with durable objective responses and promising survival outcomes in patients with previously treated small-cell lung cancer. No new safety signals were identified. (Funded by Amgen; DeLLphi-301 ClinicalTrials.gov number, NCT05060016.).

Shifting Sociodemographic Characteristics of a Phase I Clinical Trial Population at an NCI-Designated Comprehensive Cancer Center in the Southeast.

Racial and ethnic minority populations are consistently under-represented in oncology clinical trials despite comprising a disproportionate share of a cancer burden. Phase I oncology clinical trials pose a unique challenge and opportunity for minority inclusion. Here we compared the sociodemographic characteristics of patients participating in phase 1 clinical trials a National Cancer Institute ( NCI)-designated comprehensive center to all patients at the center, patients with new cancer diagnosis in metropolitan Atlanta and patients with new cancer diagnoses in the state of Georgia. From 2015 to 2020, 2325 patients (43.4% female, 56.6% male) consented to participate in a phase I trial. Grouped self-reported race distribution was 70.3% White, 26.2% Black, and 3.5% other. Of new patient registrations at Winship Cancer Institute (N = 107 497) (50% F, 50% M), grouped race distribution was 63.3% White, 32.0% Black, and 4.7% other. Patients with new cancer diagnoses in metro Atlanta from 2015 to 2016 (N = 31101) were 58.4% White, 37.2% Black, and 4.3% other. Race and sex distribution of phase I patients was significantly different than Winship patients (P < .001). Over time, percent of White patients decreased in both phase I and Winship groups (P = .009 and P < .001, respectively); percentage of females did not change in either group (P = .54 phase I, P = .063 Winship). Although phase I patients were more likely to be White, male, and privately ensured than the Winship cohort, from 2015 to 2020 the percentage of White patients in phase I trials and among all new patients treated at Winship decreased. The intent of characterizing existing disparities is to improve the representation of patients from racial and ethnic minority backgrounds in phase I clinical trials.

Cisplatin-Induced Ototoxicity: A Concise Review of the Burden, Prevention, and Interception Strategies.

Cisplatin is a bedrock of cancer management and one of the most used chemotherapeutic agents in the treatment of germ cell, lung, bladder, ovarian, and head and neck cancers. Approximately 500,000 patients diagnosed annually with these cancer types in the United States could be candidates for treatment with cisplatin. There is a 5-fold increase in the risk of hearing impairment or ototoxicity with cisplatin, which can manifest as ringing in the ear (tinnitus), high-frequency hearing loss, and at late stages, a decreased ability to hear normal conversation. More than half of adult and pediatric patients with cancer treated with cisplatin developed hearing impairment with major impact on patients' health-related quality of life. A considerable evidence gap persists regarding the burden and effective prevention and interception strategies for cisplatin-induced ototoxicity, especially in adult patients with cancer. We conducted a review of the published literature to provide an update on the status of this important clinical challenge. We also surveyed practicing oncologists within our network of academic and community practices to gain a better understanding of how the published literature compares with real-world practice. Our review of the literature showed a lack of standardized guidelines for monitoring and treatment of cisplatin-induced ototoxicity, especially in the adult cancer patient population. Our survey of practicing oncologists mirrored the findings from the published literature with a heterogeneity of practice, which highlights the need for standardization.

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.

Serum glycomic profile as a predictive biomarker of recurrence in patients with differentiated thyroid cancer.

PURPOSE: Thyroid cancer recurrence following curative thyroidectomy is associated with increased morbidity and mortality, but current surveillance strategies are inadequate for early detection. Prior studies indicate that tissue glycosylation is altered in thyroid cancer, but the utility of serum glycosylation in thyroid cancer surveillance remains unexplored. We therefore assessed the potential utility of altered serum glycomic profile as a tumor-specific target for disease surveillance in recurrent thyroid cancer. EXPERIMENTAL DESIGN: We employed banked serum samples from patients with recurrent thyroid cancer post thyroidectomy and healthy controls. N-glycans were enzymatically released from serum glycoproteins, labeled via permethylation, and analyzed by MALDI-TOF mass spectrometry. Global level and specific subtypes of glycan structures were compared between patients and controls. RESULTS: We evaluated 28 independent samples from 13 patients with cancer recurrence and 15 healthy controls. Global features of glycosylation, including N-glycan class and terminal glycan modifications were similar between groups, but three of 35 individual glycans showed significant differences. The three glycans were biosynthetically related biantennary core fucosylated N-glycans that only varied by the degree of galactosylation (G0F, G1F, and G2F; G: galactose, F: fucose). The ratio of G0F:G1F that captures reduced galactosylation was observed in patients samples but not in healthy controls (p = 0.004) and predicted thyroid cancer recurrence (AUC = 0.82, CI 95% = 0.64-0.99). CONCLUSIONS: Altered N-glycomic profile was associated with thyroid cancer recurrence. This serum-based biomarker would be useful as an effective surveillance tool to improve the care and prognosis of thyroid cancer after prospective validation.

Phase I trial of the DLL3/CD3 bispecific T-cell engager BI 764532 in DLL3-positive small-cell lung cancer and neuroendocrine carcinomas.

Poorly differentiated neuroendocrine carcinomas such as small-cell lung cancer (SCLC) have poor survival and high relapse rates. DLL3 is found on these carcinomas and has become a target of increasing interest in recent years. The bispecific DLL3/CD3 T-cell engager BI 764532 has been shown to induce complete tumor regression in a human T cell-engrafted mouse model. Here, we describe the study design of a first-in-human, phase I, multicenter, open-label, non-randomized, dose-escalation study in patients with SCLC or other DLL3-positive neuroendocrine carcinomas. The study will determine the maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics and preliminary efficacy of BI 764532 monotherapy.

DLL3 is a protein involved in development of the embryo during pregnancy. It has also been found on the surface of cells involved in the development of certain types of lung cancer and other tumors. The T-cell engager BI 764532 binds to DLL3 and cells of the immune system simultaneously, resulting in the death of tumor cells. Here we describe the rationale for, and design of, a clinical study of BI 764532 in patients with small-cell lung cancer and other tumors containing DLL3. The aim of the study is to find the highest acceptable dose of BI 764532 that can be tolerated by patients, and explore the safety and efficacy of BI 764532. Clinical Trial Registration: NCT04429087 (ClinicalTrials.gov).

A Phase 2 Study of Docetaxel, Ramucirumab, and Pembrolizumab for Patients With Metastatic or Recurrent Non-Small-Cell Lung Cancer (NSCLC) who Progressed on Platinum-Doublet and PD-1/PD-L1 Blockade.

BACKGROUND: There is an urgent and unmet need for more effective treatment options for patients with metastatic and recurrent non-small-cell lung cancer (NSCLC) who progressed on platinum-based therapy, immune checkpoint inhibitors (ICI), and targeted therapies. Currently, the combination of docetaxel (D) and ramucirumab (R) is the next best salvage therapy with a modest historical progression free survival (PFS) of 4.5 months and 6-month PFS rate of 37% predating the era of ICI use. Anecdotal reports in patients who progressed on ICI suggest a higher response rate to docetaxel compared to historical experience. Furthermore, tumor related angiogenesis promotes tumor growth and may contribute to immune escape in patients treated with ICI. Therapeutic combination with anti-angiogenic, ICI, and chemotherapy have independently demonstrated clinical efficacy without additive toxicities in NSCLC patients. PATIENTS AND METHODS: This multicenter, single arm, open label, phase 2 study will evaluate the safety and preliminary efficacy of the combination of docetaxel 75 mg/m2, ramucirumab 10 mg/kg, and pembrolizumab 200 mg in up to 41 patients with metastatic or recurrent NSCLC after progression on concomitant or sequential platinum-based chemotherapy and ICI. This treatment will be given intravenously on the same day every 3 weeks until disease progression, occurrence of severe side effects, or no clinical benefit. The primary endpoint is 6-month PFS rate. CONCLUSIONS: This is the first study to evaluate the safety and efficacy of ICI combined with docetaxel and ramucirumab. The findings could provide valuable information for developing new treatment strategies for NSCLC patients.

Concurrent Androgen Deprivation Therapy for Prostate Cancer Improves Survival for Synchronous or Metachronous Non-Small Cell Lung Cancer: A SEER-Medicare Database Analysis.

Introduction: The crosstalk between receptor kinase signaling, such as EGFR and androgen receptor signaling, suggests a potential interaction between androgen deprivation therapy (ADT) and lung cancer outcome. Methods: We employed the SEER−Medicare data of lung cancer patients diagnosed between 1988 and 2005 to test for an association between ADT for prostate cancer and lung cancer outcome. We employed the Kaplan−Meier method and Cox proportional hazard with log-rank test model to assess any significant impact of ADT on survival. Results: We included data from 367,750 lung cancer patients; 17.4%, 2.9%, 33.6% and 46.1% with stages I, II, III and IV, respectively; 84.5% were >65 years; 57.2% males; 84.2% Caucasians and 9.3% Blacks. There were 11,061 patients (3%) with an initial prostate cancer diagnosis followed by lung cancer (P-L group); 3017 (0.8%) with an initial diagnosis of lung cancer and subsequent prostate cancer diagnosis (L-P group); the remainder had only lung cancer (L group). Stage I lung cancer was most common in the L-P group compared to the L and P-L groups­54% vs. 17.13% vs. 17.92%, p < 0.0001 for L-P, L and P-L, respectively. The median OS for lung cancer diagnosis was 93 months versus 10 and 9 months, respectively, for the L-P, L and P-L subgroups. ADT was associated with improved survival on multivariate analysis, especially in Caucasian patients (HR of death: 0.86; 95% CI: 0.76−0.97; p = 0.012). Conclusion: ADT was associated with improved outcome for NSCLC, in line with the hypothesis of a role for the androgen receptor in lung cancer. Our findings support a systematic evaluation of the potential benefit of ADT as a therapy for lung cancer.

MERTK activation drives osimertinib resistance in EGFR-mutant non-small cell lung cancer.

Acquired resistance is inevitable in non-small cell lung cancers (NSCLCs) treated with osimertinib (OSI), and the mechanisms are not well defined. The MERTK ligand GAS6 promoted downstream oncogenic signaling in EGFR-mutated (EGFRMT) NSCLC cells treated with OSI, suggesting a role for MERTK activation in OSI resistance. Indeed, treatment with MRX-2843, a first-in-class MERTK kinase inhibitor, resensitized GAS6-treated NSCLC cells to OSI. Both GAS6 and EGF stimulated downstream PI3K/AKT and MAPK/ERK signaling in parental cells, but only GAS6 activated these pathways in OSI-resistant (OSIR) derivative cell lines. Functionally, OSIR cells were more sensitive to MRX-2843 than parental cells, suggesting acquired dependence on MERTK signaling. Furthermore, MERTK and/or its ligands were dramatically upregulated in EGFRMT tumors after treatment with OSI in both xenograft models and patient samples, consistent with induction of autocrine/paracrine MERTK activation. Moreover, treatment with MRX-2843 in combination with OSI, but not OSI alone, provided durable suppression of tumor growth in vivo, even after treatment was stopped. These data identify MERTK as a driver of bypass signaling in treatment-naive and EGFRMT-OSIR NSCLC cells and predict that MRX-2843 and OSI combination therapy will provide clinical benefit in patients with EGFRMT NSCLC.

A Multicenter Randomized Phase II Study of Single Agent Efficacy and Optimal Combination Sequence of Everolimus and Pasireotide LAR in Advanced Thyroid Cancer.

PURPOSE: Aberrant mTOR pathway and somatostatin receptor signaling are implicated in thyroid cancer and offer potential therapeutic targets. We assessed the clinical efficacy of everolimus and Pasireotide long-acting release (LAR) in radioiodine-refractory differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC). PATIENTS AND METHODS: Adults with progressive MTC and DTC untreated or treated with no more than one systemic agent were eligible. The trial was designed to establish the most promising regimen and the optimal combination sequence. Patients were randomized to start treatment with single agent everolimus (10 mg QD; Arm A), pasireotide-LAR (60 mg intramuscular injection, Q4 weeks; Arm B), or the combination (Arm C). At initial progression (PFS1), patients on Arm A or B switched to the combination and continued until progression (PFS2). Efficacy was measured by RECIST criteria. RESULTS: Study enrolled 42 patients: median age 65 years; female 17 (40.5%); White 31 (73.8%), African American 6 (14.3%), others 5 (11.9); DTC 32 (76.2%); MTC 10 (23.8%). There was no objective response by RECIST criteria across the three arms. Median and 1-year PFS1 rates were 8.3, 1.8, 8.1 months and 49.9%, 36.4%, 25.0% for Arms A, B, C, respectively. Median and 1-year PFS2 rates were 26.3, 17.5, 8.1 months and 78.4%, 70.0%, 25% for Arms A, B, C, respectively. The most frequent adverse events were anemia, stomatitis, fatigue, hyperglycemia, and hypercholesterolemia. CONCLUSIONS: The combination of everolimus and pasireotide-LAR showed promising efficacy over single agent. The delayed combination of everolimus and pasireotide-LAR following progression on single agent everolimus appeared intriguing as a combination strategy.

Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.

Comprehensive sequencing of patient tumors reveals genomic mutations across tumor types that enable tumorigenesis and progression. A subset of oncogenic driver mutations results in neomorphic activity where the mutant protein mediates functions not engaged by the parental molecule. Here, we identify prevalent variant-enabled neomorph-protein-protein interactions (neoPPI) with a quantitative high-throughput differential screening (qHT-dS) platform. The coupling of highly sensitive BRET biosensors with miniaturized coexpression in an ultra-HTS format allows large-scale monitoring of the interactions of wild-type and mutant variant counterparts with a library of cancer-associated proteins in live cells. The screening of 17,792 interactions with 2,172,864 data points revealed a landscape of gain of interactions encompassing both oncogenic and tumor suppressor mutations. For example, the recurrent BRAF V600E lesion mediates KEAP1 neoPPI, rewiring a BRAFV600E/KEAP1 signaling axis and creating collateral vulnerability to NQO1 substrates, offering a combination therapeutic strategy. Thus, cancer genomic alterations can create neo-interactions, informing variant-directed therapeutic approaches for precision medicine.

Assessment of hyperprogression versus the natural course of disease development with nivolumab with or without ipilimumab versus placebo in phase III, randomized, controlled trials.

BACKGROUND: Retrospective studies have suggested a potential risk of hyperprogressive disease (HPD) in patients receiving immune checkpoint inhibitors (ICIs). We compared the incidence of HPD during treatment with nivolumab±ipilimumab versus natural tumor progression with placebo in post hoc analyses of two randomized, double-blind clinical trials. METHODS: ATTRACTION-2 randomized patients with advanced gastric or gastroesophageal junction cancer (GC/GEJC) and progression on ≥2 prior regimens to nivolumab 3 mg/kg Q2W or placebo. CheckMate 451 randomized patients with extensive-disease small cell lung cancer (ED SCLC) and ongoing complete/partial response or stable disease after first-line chemotherapy to nivolumab 240 mg Q2W, nivolumab 1 mg/kg+ipilimumab 3 mg/kg Q3W for four doses then nivolumab 240 mg Q2W, or placebo. Patients receiving ≥1 dose of study drug and with tumor scans at baseline and the first on-treatment evaluation were included in the HPD analyses. HPD definitions were ≥20%, ≥50%, and ≥100% increase in target lesion sum of the longest diameters (SLD) at the first on-treatment assessment. RESULTS: In the ATTRACTION-2 HPD-evaluable population, 243 patients received nivolumab and 115 placebo. Fewer patients receiving nivolumab versus placebo had increases in SLD ≥20% (33.7% vs 46.1%) and ≥50% (6.2% vs 11.3%); similar proportions had increases in SLD ≥100% (1.6% vs 1.7%). In the CheckMate 451 HPD-evaluable population, 177 patients received nivolumab, 179 nivolumab+ipilimumab, and 175 placebo. Fewer patients receiving nivolumab or nivolumab+ipilimumab versus placebo had increases in SLD ≥20% (27.1%, 27.4% vs 45.7%), ≥50% (10.2%, 11.2% vs 22.3%), and ≥100% (2.8%, 2.8% vs 6.3%). CONCLUSIONS: Nivolumab±ipilimumab was not associated with an increased rate of progression versus placebo in patients with GC, GEJC, or ED SCLC, suggesting that previous reports of HPD may reflect the natural disease course in some patients rather than ICI-mediated progression. TRIAL REGISTRATION NUMBER: NCT02538666; NCT02267343.

Overcoming acquired resistance to third-generation EGFR inhibitors by targeting activation of intrinsic apoptotic pathway through Mcl-1 inhibition, Bax activation, or both.

Treatment of EGFR-mutant non-small cell lung cancer (NSCLC) with mutation-selective third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib has achieved remarkable success in the clinic. However, the immediate challenge is the emergence of acquired resistance, limiting the long-term remission of patients. This study suggests a novel strategy to overcome acquired resistance to osimertinib and other third-generation EGFR-TKIs through directly targeting the intrinsic apoptotic pathway. We found that osimertinib, when combined with Mcl-1 inhibition or Bax activation, synergistically decreased the survival of different osimertinib-resistant cell lines, enhanced the induction of intrinsic apoptosis, and inhibited the growth of osimertinib-resistant tumor in vivo. Interestingly, the triple-combination of osimertinib with Mcl-1 inhibition and Bax activation exhibited the most potent activity in decreasing the survival and inducing apoptosis of osimertinib-resistant cells and in suppressing the growth of osimertinib-resistant tumors. These effects were associated with increased activation of the intrinsic apoptotic pathway evidenced by augmented mitochondrial cytochrome C and Smac release. Hence, this study convincingly demonstrates a novel strategy for overcoming acquired resistance to osimertinib and other 3rd generation EGFR-TKIs by targeting activation of the intrinsic apoptotic pathway through Mcl-1 inhibition, Bax activation or both, warranting further clinical validation of this strategy.

Telaglenastat Plus Cabozantinib or Everolimus for Advanced or Metastatic Renal Cell Carcinoma: An Open-Label Phase I Trial.

PURPOSE: Dual inhibition of glucose and glutamine metabolism results in synergistic anticancer effects in solid tumor models. Telaglenastat, an investigational, small-molecule, glutaminase inhibitor, exhibits modest single-agent activity in renal cell carcinoma (RCC) patients. This phase Ib trial evaluated telaglenastat plus cabozantinib or everolimus, agents known to impair glucose metabolism in patients with metastatic RCC (mRCC). PATIENTS AND METHODS: mRCC patients received escalating doses of telaglenastat [400-800 mg per os (p.o.) twice daily] in a 3 + 3 design, plus either everolimus (10 mg daily p.o.; TelaE) or cabozantinib (60 mg daily p.o.; TelaC). Tumor response (RECISTv1.1) was assessed every 8 weeks. Endpoints included safety (primary) and antitumor activity. RESULTS: Twenty-seven patients received TelaE, 13 received TelaC, with median 2 and 3 prior therapies, respectively. Treatment-related adverse events were mostly grades 1 to 2, most common including decreased appetite, anemia, elevated transaminases, and diarrhea with TelaE, and diarrhea, decreased appetite, elevated transaminases, and fatigue with TelaC. One dose-limiting toxicity occurred per cohort: grade 3 pruritic rash with TelaE and thrombocytopenia with TelaC. No maximum tolerated dose (MTD) was reached for either combination, leading to a recommended phase II dose of 800-mg telaglenastat twice daily with standard doses of E or C. TelaE disease control rate (DCR; response rate + stable disease) was 95.2% [20/21, including 1 partial response (PR)] among 21 patients with clear cell histology and 66.7% (2/3) for papillary. TelaC DCR was 100% (12/12) for both histologies [5/10 PRs as best response (3 confirmed) in clear cell]. CONCLUSIONS: TelaE and TelaC showed encouraging clinical activity and tolerability in heavily pretreated mRCC patients.

Induction of SREBP1 degradation coupled with suppression of SREBP1-mediated lipogenesis impacts the response of EGFR mutant NSCLC cells to osimertinib.

Emergence of acquired resistance to osimertinib (AZD9291), the first-approved third-generation EGFR inhibitor that selectively and irreversibly inhibits the activating EGFR mutations and the resistant T790M mutation, is a giant and urgent clinical challenge. Fully understanding the biology underlying the response of EGFR mutant non-small cell lung cancer (NSCLC) to osimertinib is the foundation for development of mechanism-driven strategies to overcome acquired resistance to osimertinib or other third-generation EGFR inhibitors. This study focused on tackling this important issue by elucidating the critical role of sterol regulatory element-binding protein 1 (SREBP1) degradation in conferring the response of EGFR mutant NSCLC cells to osimertinib and by validating the strategy via directly targeting SREBP1 for overcoming osimertinib acquired resistance. Osimertinib facilitated degradation of the mature form of SREBP1 (mSREBP1) in a GSK3/FBXW7-dependent manner and reduced protein levels of its regulated genes in EGFR-mutant NSCLC cells/tumors accompanied with suppression of lipogenesis. Once resistant, EGFR-mutant NSCLC cell lines possessed elevated levels of mSREBP1, which were resistant to osimertinib modulation. Both genetic and pharmacological inhibition of SREBP1 sensitized osimertinib-resistant cells and tumors to osimertinib primarily through enhancing Bim-dependent induction of apoptosis, whereas enforced expression of ectopic SREBP1 in sensitive EGFR-mutant NSCLC cells compromised osimertinib's cell-killing effects. Collectively, we have demonstrated a novel connection between osimertinib and SREBP1 degradation and its impact on the response of EGFR mutant NSCLC cells to osimertinib and suggested an effective strategy for overcoming acquired resistance to osimertinib, and possibly other EGFR inhibitors, via targeting SREBP1.

Advances in Treatment of Recurrent Small Cell Lung Cancer (SCLC): Insights for Optimizing Patient Outcomes from an Expert Roundtable Discussion.

Second-line treatment options for patients with relapsed, extensive-stage small cell lung cancer (ES-SCLC) are limited, and even with currently available treatments, prognosis remains poor. Until recently, topotecan (a topoisomerase I inhibitor) was the only drug approved by the United States (US) Food and Drug Administration (FDA) for the management of ES-SCLC following progression after first-line treatment with etoposide plus a platinum derivative (EP; carboplatin preferred). With the most recent approval of EP plus a programmed death ligand 1 (PD-L1) inhibitor, there are now more therapeutic options for managing ES-SCLC. A number of novel agents have emerging data for activity in relapsed ES-SCLC, and single-agent lurbinectedin (an alkylating drug and selective inhibitor of oncogenic transcription and DNA repair machinery in tumor cells) has conditional FDA approval for use in this patient population. Trilaciclib, a short-acting cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor, has also been recently approved as a supportive intervention for use prior to an EP or a topotecan-containing regimen to diminish the incidence of chemotherapy-induced myelosuppression. The current review is based on a recent expert roundtable discussion and summarizes current therapeutic agents and emerging data on newer agents and biomarkers. It also provides evidence-based clinical considerations and a treatment decision tool for oncologists treating patients with relapsed ES-SCLC. This paper discusses the importance of various factors to consider when selecting a second-line treatment option, including prior first-line treatment, available second-line treatment options, tumor platinum sensitivity, and patient characteristics (such as performance status, comorbidities, and patient-expressed and perceived values).

Physician Communication and Patient Understanding of Molecular Testing Terminology.

BACKGROUND: The use of molecular testing in oncology is rapidly expanding. The aim of this study was to determine how oncologists describe molecular testing and whether patients understand the terminology being used. MATERIALS AND METHODS: Sixty conversations between oncologists and patients about molecular testing were observed, and the used technical terms were noted by the researcher. Patients were interviewed post-conversation to assess their understanding of the noted technical terms. A patient understanding score was calculated for each participant. Comparisons of the terms were conducted using χ2 tests, Fisher's exact tests, or ANOVA when appropriate. RESULTS: Sixty-one unique technical terms were used by oncologists, to describe seven topics. "Mutation" was a challenging term for patients to understand with 48.8% (21/43 mentions) of participants correctly defining the term. "Genetic testing" and "Gene" were understood a little more than half the time (53.3%; 8/15 and 56.4%; 22/39 respectively). "DNA" was well understood (80%; 12/15). There was no correlation between the terms being defined by the oncologist in the conversation, and the likelihood of the patient providing a correct definition. White participants were significantly more likely to understand both "mutation" and "genetic testing" than non-White participants. Forty-two percent (n = 25) of participants had an understanding score below 50%, and a higher family income was significantly correlated with a higher score. CONCLUSION: Our results show that oncologists use variable terminology to describe molecular testing, which is often not understood. Because oncologists defining the terms did not correlate with understanding, it is imperative to develop new, improved methods to explain molecular testing. IMPLICATIONS FOR PRACTICE: The use of molecular testing is expanding in oncology, yet little is known about how effectively clinicians are communicating information about molecular testing and whether patients understand the terminology used. The results of this study indicate that patients do not understand some of the terminology used by their clinicians and that clinicians tend to use highly variable terminology to describe molecular testing. These results highlight the need to develop and implement effective methods to explain molecular testing terminology to patients to ensure that patients have the tools to make autonomous and informed decisions about their treatment.

Discovery of Small Molecule Bak Activator for Lung Cancer Therapy.

Rationale: Bak is a major proapoptotic Bcl2 family member and a required molecule for apoptotic cell death. High levels of endogenous Bak were observed in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cell lines. Increased Bak expression was correlated with poor prognosis of NSCLC patients, suggesting that Bak protein is an attractive target for lung cancer therapy. The BH3 domain functions as death domain and is required for Bak to initiate apoptotic cell death. Thus, the BH3 domain is attractive target for discovery of Bak agonist. Methods: The BH3 death domain binding pocket (aa75-88) of Bak was chosen as a docking site for screening of small molecule Bak activators using the UCSF DOCK 6.1 program suite and the NCI chemical library (300,000 small molecules) database. The top 500 compounds determined to have the highest affinity for the BH3 domain were obtained from the NCI and tested for cytotoxicity for further screening. We identified a small molecule Bak activator BKA-073 as the lead compound. The binding affinity of BKA-073 with Bak protein was analyzed by isothermal titration calorimetry (ITC) assay. BKA-073-mediated Bak activation via oligomerization was analyzed by a cross-linking with Bis (maleimido) hexane (BMH). Sensitivity of BKA-073 to lung cancer cells in vitro was evaluated by dynamic BH3 profiling (DBP) and apoptotic cell death assay. The potency of BKA-073 alone or in combination with radiotherapy or Bcl2 inhibitor was evaluated in animal models. Results: We found that BKA-073 binds Bak at BH3 domain with high affinity and selectivity. BKA-073/Bak binding promotes Bak oligomerization and mitochondrial priming that activates its proapoptotic function. BKA-073 potently suppresses tumor growth without significant normal tissue toxicity in small cell lung cancer (SCLC) and NSCLC xenografts, patient-derived xenografts, and genetically engineered mouse models of mutant KRAS-driven cancer. Bak accumulates in radioresistant lung cancer cells and BKA-073 reverses radioresistance. Combination of BKA-073 with Bcl-2 inhibitor venetoclax exhibits strong synergy against lung cancer in vivo. Conclusions: Development of small molecule Bak activator may provide a new class of anticancer agents to treat lung cancer.