bluuebunny/crossref_metadata_2025 huggingface dataset:
Young adults (YA) with non-small cell lung cancer (NSCLC): Snapshot of the oncogenic drivers and immune landscapes.
Authors: Pruitt Aaron , Hsu Robert , Gandhi Nishant , Olazapasti Coral , Rodriguez Estelamari , Owen Dwight Hall , Gheeya Jinesh , Zhang Jun , Furqan Muhammad , LoPiccolo Jaclyn , Elliott Andrew , VanderWalde Ari , Rock Stephanie , Ma Patrick C. , Halmos Balazs , Hao Zhonglin
Published: June 2024

8538

Background: Approximately 5% of NSCLC occurs in patients 50 years or younger (median age:71) representing distinct clinicopathological features. Reports characterizing genomic alterations are scarce. Using a large real-world (RW) dataset, we characterize oncogenic drivers, and immune landscapes to better understand YA with NSCLC. Methods: 42,326 NSCLC specimens were analyzed using next-generation sequencing of DNA (DNA-592 panel or whole exome) or RNA (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). YA (<=50 years) were categorized into three groups (years): 18-30 (A1, n=61), 31-40 (A2, n=277) & 41-50 (A3, n=1,549); vs >50 (A4, n=40,439). Composition of tumor microenvironment (TME) was estimated from bulk RNA sequencing using QuanTIseq method. RW survival on Osimertinib (Osi-OS) was obtained from insurance claims and calculated from initiation of Osi treatment to last contact and was compared between ages 18-50 and >50 years. Hazard ratio (HR) was calculated using the Cox proportional hazards model. Statistical significance was determined using Chi-square, Fisher’s Exact, Mann-Whitney U and log-rank tests and corrected for multiple comparisons where applicable (q<0.05). Results: Consistent with previous reports, NSCLC in YA was more prevalent in females, non-smokers and was associated with adenocarcinoma histology. Among driver alterations, ALK(IHC+), ROS1, RET and NTRK1 fusion were enriched and KRAS mutations were reduced in YA. Interestingly, while the prevalence of KRASG12D from transition (non-smoker related) and EGFRE746_A750 decreased with age, KRASG12C from transversion increased with age in YA. YA were also associated with improved Osi-OS (HR: 0.79, median Osi-OS=37.4 months vs 32 months in >50 years old, p=0.019). High tumor mutation burden (>=10 mut/Mb), the prevalence of mutations in TP53, KMT2D, NF1, RBM10, NFE2L2 and NOTCH1 increased while GNAS decreased with age. The expression of immune checkpoint genes such as PDCD1LG2(A1/A4: 0.63, A3/A4: 0.89), LAG3(A2/A4: 0.73, A3/A4: 0.89) and IFNG (A1/A4: 0.32, A3/A4: 0.75) were reduced, while M2 macrophage (A2/A4: 1.2) and neutrophil (A2/A4: 1.2) were increased in YA (all q<0.05). Conclusions: We report an increased prevalence of RET and NTRK1 fusions in YA and key differences in distributions of frequent KRAS and EGFR mutations in YA (vs A4) along with decreased expression of immune related genes in the tumor microenvironment. The implications are under active investigation. [Table: see text]
Impact of maintenance pemetrexed cessation on clinical outcomes of patients with metastatic non-squamous NSCLC.
Authors: Bhatia Shreya , Iams Wade Thomas , Lu Matthew , Lessans Spencer , Libre Michael
Published: June 2024

8568

Background: Combination chemoimmunotherapy including pemetrexed and a PD(L)1 inhibitor is a common first line systemic approach for patients with metastatic non-squamous non-small cell lung cancer (NSCLC). Patients often discontinue maintenance pemetrexed due to adverse effects, and little is known about the impact of maintenance pemetrexed cessation on progression free survival (PFS) and overall survival (OS). Methods: 121 patients with stage IV or recurrent, metastatic non-squamous NSCLC treated at VUMC were included in this retrospective analysis. Patients diagnosed between 7/2017- 9/2023 were included if they received maintenance pemetrexed and pembrolizumab. Patients were divided into two groups: those who stopped pemetrexed due to toxicity and those who did not. PFS and OS were measured from time of stage IV or metastatic diagnosis to the date of radiographic progression or death, respectively, and compared with the Kaplan Meier method. Results: Among patients with stage IV or recurrent, metastatic NSCLC (n = 121), who remained on maintenance pemetrexed and pembrolizumab (n=68), the median PFS was 11.7 months (95% CI, 7.47-NA) compared to 24.3 months (95% CI, 19.4-NA) among patients who stopped maintenance pemetrexed (n=53; p=0.1). The median OS in the same patient groups was 25.8 months (95% CI, 13.8-NA) compared to 36.4 months (95% CI, 26.9-NA) (p=0.15), respectively. Among patients with stage IV disease at diagnosis (n = 97), the median PFS among patients who did not stop pemetrexed was 8.7 months (95% CI, 7.2–NA) compared to 24.3 months (95% CI, 17.3-NA) for patients who stopped pemetrexed (p=0.089). The median OS in these groups were 21 months (95% CI, 13.6-NA) and 38.6 months (95%, 28.0-NA) (p=0.054), respectively. Conclusions: In this study of patients with metastatic non-squamous NSCLC who received maintenance pemetrexed and pembrolizumab, patients who stopped pemetrexed due to toxicity experienced similar outcomes to those who continued with pemetrexed. The necessity of continuation of maintenance chemotherapy should be further evaluated in the immunotherapy era. [Table: see text]
Metabolic profile and therapeutic vulnerabilities of multi-omic characterization ofKRAS/STK11/KEAP1 co-mutant non–small cell lung cancer (NSCLC).
Authors: Sen Triparna , Sen Utsav , Coleman Charles , Elliott Andrew , Hasson Dan , Vanderwalde Ari M. , Ma Patrick C. , Gandhi Nishant , Halmos Balazs
Published: June 2024

8576

Background: KRAS-mutant NSCLC with co-occurring loss-of-function mutations in STK11 and KEAP1(KSK) are remarkably aggressive and poorly responsive to chemo- and immunotherapy. Novel therapeutic strategies are urgently needed to improve outcomes for patients with KRAS/STK11/KEAP1co-mutant NSCLC (KSK). We interrogated the transcriptomic landscape using a large real-world dataset of NSCLC to identify therapeutic vulnerabilities that may help guide treatment selections in KSK. Methods: KRAS mutant NSCLC clinical samples (N=7210) were tested with NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) at Caris Life Sciences (Phoenix, AZ). Specimens were stratified into KRASMUT/STK11MUT/KEAP1MUT (KSK; N=698), KRASMUT/STK11MUT/KEAP1WT (KS; N=786), KRASMUT/STK11WT/KEAP1MUT (KK; N=466), and KRASMUT/STK11WT/KEAP1WT (K; N=4536). Real-world overall survival (OS) data was obtained from insurance claims and investigated using Kaplan-Meier estimates. Additionally, an in vitro CRISPR screen, bulk RNA sequencing, and phospho-kinase arrays were performed in KRAS/STK11/KEAP1 co-mutant, single mutant, and wild-type cell lines to better characterize these models. Results: KEAP1mutations (median OS: KK=7.83 months, KSK=7.23 months) were strongly associated with poor OS compared to STK11 mutations (median OS: KS=17.6months). Pathways significantly upregulated in KSK clinical samples included fatty acid metabolism and redox pathways. When compared to single mutant or wild-type conditions, KSK clinical samples had significant up-regulation of genes involved in ferroptosis evasion and metabolism like SLC7A11(KSK/KK=1.28, KSK/KS=4.82, KSK/K=10.24; all q<0.01) and SCD1(KSK/KS=1.19, KSK/K=1.24; both q<0.01). To confirm our clinical findings, CRISPR/Cas9-based genetic screening identified SCD1, and SLC7A11 master regulators of fatty acid metabolism and ferroptosis, as a potential therapeutic target in the KSK cell lines. SCD1 inhibition augmented the effect of ferroptosis inducer, erastin. Targeting SCD1 led to global metabolomic changes in KSK cells, including key pathways involved in lipid and glucose metabolismas compared to single mutants or wild-type cells. Finally, pharmacological inhibition of SCD1 caused significant tumor regression and augmented the anti-tumor response of SLC7A11 inhibitor, imidazole ketone erastin (IKE), in KSK syngeneic mouse models. Conclusions: Our study is the first to highlight the importance of the ferroptosis regulators, SCD1-SLC7A11,in regulating unique metabolic and ferroptosis evasion pathways in KSK patient tumor and preclinical models. The study data furthers the understanding of ferroptosis in NSCLCand the potential to translate SCD1 inhibitors and ferroptosis inducers in KRAS NSCLC clinical trials.
Detection of comprehensive oncogenic driver alteration of non-small cell lung cancer from cytology specimens by multi-gene PCR panel.
Authors: Sakai Tetsuya , Izumi Hiroki , Matsumoto Shingo , Udagawa Hibiki , Tanaka Yu , Sugiyama Eri , Umemura Shigeki , Zenke Yoshitaka , Yoh Kiyotaka , Goto Koichi
Published: June 2024

8579

Background: The analysis of the next-generation sequencing (NGS) panel test requires a sufficient amount of tissue specimens (TS), but the collection of tissue specimens can be sometimes challenging in clinical practice. Despite being easier and safer to collect than TS, cytology specimens (CS) are considered unsuitable for NGS due to the small number of tumor cells. The AmoyDx Pan Lung Cancer PCR Panel (AmoyDx), a multi-gene PCR panel that amplified mutation or fusion variants of 11 genes (EGFR, ALK, ROS1, RET, MET HER2, BRAF, KRAS, and NTRK1-3) by real-time PCR, can be performed with smaller amounts of nucleic acid than NGS, and CS may be suitable for multi-gene analysis using this panel. In this study, we evaluated the feasibility of multi-gene analysis using CS, and the concordance rate of gene alteration between CS and TS in non–small cell lung cancer (NSCLC). Methods: We enrolled consecutive NSCLC patients obtaining CS through bronchoscopy, including transbronchial brushing (TBB) and transbronchial needle aspiration (TBNA) from September 2020 to March 2023. These CS were preserved as frozen pellets. The difference in the amount of nucleic acid, the success rate and the concordance rate of gene alteration with AmoyDx were evaluated between CS and pared TS collected simultaneously with CS. Results: A total of 131 (Ad/Sq/NSCLC-NOS: 113/2/16) cases were enrolled in this study. Fifty-nine specimens were obtained through TBB and another 72 were obtained through TBNB. The median nucleic acid concentration (NanoDrop [ng/μL]) isolated from CS was comparable to that isolated from TS (DNA 114/99, p=0.96; RNA 36/27, p=0.63). However, the median DNA concentration in CS was significantly lower (80/102, p=0.01) in TBB samples, while in TBNA samples, it was higher (134/90, p=0.03). Almost all CS (99.2%,130/131) and TS (99.2%,130/131) were analyzed successfully with AmoyDx, with only one RNA analysis failure in each group. Among CS, 78 (60%) samples exhibit gene alteration, including EGFR/KRAS/BRAF/HER2/ALK/ROS1/MET/RET: 44/9/2/5/8/1/8/1, while 77 (59%); 44/9/2/6/6/1/8/1 in TS. The positive percent agreement, negative percent agreement, and overall percent agreement of CS using analysis compared with the results of TS using analysis were 99% (76/77), 96% (52/54), and 98% (128/131), respectively. Conclusions: CS exhibit an extremely high success rate for multi-gene analysis, with nucleic acid yield comparable to TS. Moreover, the concordance rate of gene alteration between CS and TS is also remarkably high. CS emerge as a viable alternative to TS for analyzing driver gene alteration in multi-gene PCR analysis.
Sacituzumab govitecan (SG) + pembrolizumab (pembro) in first-line (1L) metastatic non-small cell lung cancer (mNSCLC) with PD-L1 ≥ 50%: Cohort A of EVOKE-02.
Authors: Patel Jyoti D. , Cho Byoung Chul , Cobo Manuel , Reyes Cabanillas Roxana , Vicente David , Fuentes Pradera Jose , Garon Edward B. , Mok Tony S. K. , Cappuzzo Federico , Neal Joel W. , Mekan Sabeen Fatima , Safavi Farnoush , Fernando Nelumka , Chisamore Michael Jon , Reck Martin
Published: June 2024

8592

Background: SG, a Trop-2–directed antibody-drug conjugate, has clinical activity and manageable safety in heavily pretreated patients with mNSCLC. EVOKE-02 (NCT05186974) is an ongoing, global, open-label, multicohort phase 2 study evaluating SG + pembro ± platinum agent as 1L treatment for mNSCLC. We report safety and efficacy results from Cohort A of EVOKE-02, with a median follow-up of 11.3 months. Methods: Patients aged ≥18 years with no prior systemic mNSCLC treatment, no actionable genomic alterations, and an ECOG performance status of 0 or 1 were enrolled into Cohort A [PD-(L)1 tumor proportion score ≥50%, 22C3 assay]. Patients received SG 10 mg/kg intravenously on days 1 and 8 + pembro 200 mg intravenously on day 1 of 21-day cycles. Primary endpoints include objective response rate (ORR; RECIST v1.1) per independent review committee (IRC); secondary endpoints include progression-free survival (PFS), duration of response (DOR), disease control rate (all per IRC), overall survival (OS), and safety. Results: As of December 1, 2023, 30 patients in Cohort A were enrolled and had received SG + pembro. Median age was 67 (range, 47-77) years; 60% had nonsquamous histology and 80% had an ECOG performance status of 1. Among all treated patients (n=30), ORR was 67% (95% CI, 47-83%) (squamous, 67% [95% CI, 35-90%]; nonsquamous, 67% [95% CI, 41-87%]). Median PFS was 13.1 (95% CI, 5.5-not reached [NR]) months (squamous, NR [95% CI, 1.2-NR] months; nonsquamous, 13.1 [95% CI, 5.5-NR] months). Median DOR was NR. In the safety population (n=30), the incidence of grade ≥3 treatment-emergent adverse events (TEAEs) and of grade ≥3 TEAEs related to any study drug were 67% and 40%, respectively. Grade ≥3 TEAEs in ≥10% of patients were neutropenia (17%), diarrhea (10%), and respiratory failure (10%). TEAEs leading to SG discontinuation occurred in 17%. There was 1 (3%) treatment-related death due to neutropenic sepsis. Conclusions: SG + pembro demonstrated promising activity in patients with tumor proportion score ≥50% mNSCLC. AEs were manageable and consistent with the known safety profile of each individual agent. The EVOKE-03 study (NCT05609968) of pembro vs SG + pembro in mNSCLC is ongoing. Clinical trial information: NCT05186974 . [Table: see text]
Lung cancer MDT quality assessment: A nationwide study.
Authors: Berg Janna , Aamelfot Christina , Aanes Siv-Gyda , Wilskow Marit , Bjaanæs Maria Moksnes , Brustugun Odd Terje , Fluge Sverre , Flåtten Per Andersen , Gronberg Bjorn Henning , Skraastad Terje , van Helvoirt Rene P , Petersen Martin , Tilseth Rune , Rasmussen Torben Riis , Neumann Kirill
Published: June 2024

8594

Background: This observational study evaluates concordance between lung cancer multi-disciplinary team (MDT) meetings, focusing on diagnosis, staging, and treatment recommendations, especially for curative options. Assessing MDT decisions aims to identify factors potentially affecting survival rates, promoting equal treatment access for patients nationwide. Methods: In Norway, patients with lung cancer are discussed at local MDT (without a thoracic surgeon present) and at university hospital MDT (with a thoracic surgeon present). All hospitals received 35 fictitious case reports of patients with inoperable non-small cell (NSCLC) and small cell lung cancer (SCLC) with anonymized CT and PET images for discussion at the ordinary MDT meetings. Of the 12 participating hospitals, 5 were university hospitals. Results: Of the 35 patient’s cases, 12 were assessed as having stage III NSCLC. For 10 of the 12 there were differences in stage assessment, from stage IIIA-B-C to IV, and in recommended treatment (Table). For each case, curative treatment was recommended by a varying number of MDTs, from zero to nine of 12. Treatment suggestions for the four SCLC patients were identical except for one patient with stage IV, performance status (PS) score 2-3 and stroke, for whom the recommended treatment ranged from best supportive care (BSC) to triple therapy. There was generally good consensus between recommending treatment with a tyrosine kinase inhibitor (TKI) in patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) translocation positivity. We found that factors leading to discrepancies in MDT decisions were patients age >75-80 years, comorbidities, PS 2 or lack of a stated PS, PD-L1 more than 50-75% in stage IV and large cell neuroendocrine carcinoma (LNEC). Conclusions: MDT-recommendations regarding treatment varied between MDT sites, and this may have the greatest consequences for patients in stage III. MDT treatment recommendations varied between the sites, confirming that treatment choice can be challenging in certain type of cases like elderly, poor PS or LNEC. Shared decision-making (SDM) with patients was often recommended. As an important outcome of the study, we found no difference in treatment choice between local and university hospital MDTs. [Table: see text]
FDA analysis of immune checkpoint inhibitors in combination with vascular endothelial growth factor tyrosine kinase inhibitors in the second-line treatment of patients with advanced non-small cell lung cancer.
Authors: Malinou Justin Nathaniel , Mehta Gautam , Vellanki Paz J. , Larkins Erin A. , Kluetz Paul Gustav , Singh Harpreet
Published: June 2024

8595

Background: Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 in combination with platinum-based chemotherapy is standard first-line therapy for patients with advanced non-small cell lung cancer (NSCLC). The majority of these patients progress and there remains a high unmet medical need in the second-line setting given the limited FDA approved available therapies. The ICI plus vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI) combination, successful across several tumor types, was studied in NSCLC as a potential treatment option. Methods: The FDA identified 3 randomized trials conducted between June 2019 and August 2023, comparing the combination regimen ICI plus VEGF TKI to docetaxel in patients with advanced NSCLC who had progressed on both platinum-based chemotherapy and an ICI. All 3 trials were publicly reported to have not met their primary endpoint. Topline results for key efficacy and safety outcomes from each of the 3 trials were provided by the commercial sponsors. Results: 1317 total patients across 3 trials (LEAP-008, SAPPHIRE and CONTACT-01) were randomized to receive either an ICI plus VEGF TKI or docetaxel. The results are presented (Table). Efficacy parameters demonstrated similar results across trials between arms. There was no clear signal that the combination is more effective than single agent docetaxel. Safety parameters across trials consistently demonstrated higher rates of toxicity with the combination. Conclusions: ICI plus oral VEGF TKI combinations have not demonstrated an advantage over docetaxel in randomized trials of patients with advanced NSCLC. In 2 of the 3 trials, response rate data did not demonstrate superior efficacy compared to docetaxel. Additionally, any observed PFS benefit was small in magnitude. The relatively low efficacy, in combination with the additive toxicity of the regimen, may curtail a potential OS benefit. There remains a high unmet medical need in this patient population and further analysis is necessary to explore potential NSCLC subgroups which may derive benefit. [Table: see text]
Efficacy and safety of MCLA-129, an EGFR/c-MET bispecific antibody, in advanced non-small cell lung cancer (NSCLC).
Authors: Wang Jie , Zhong Jia , Wu Lin , Chen Bolin , Wang Zhe-Hai , Yao Yu , Dong Xiaorong , Li Wei , Ren Xiubao , Hou Xiaoming , Zang Ai-min , Qu Xiujuan , Zhang Guojun , Wang Yongsheng , Bai Yuansong , Liu Linlin , Yu Guohua , Chen Xingwu , Ding Lieming
Published: June 2024

8604

Background: MCLA-129 is a common light chain, Biclonics, bispecific antibody targeting EGFR and c-MET with enhanced antibody-dependent cellular cytotoxicity. Here we describe the ongoing first-in-human phase 1/2 study of MCLA-129 in patients with NSCLC, including patients with MET exon 14 skipping (METex14) mutation (cohort A), EGFR exon 20 insertion (exon20ins)-mutated (cohort B) and sensitized EGFR-mutated disease (cohort C). Methods: Patients received MCLA-129 (100–2000 mg) IV biweekly or 1000-1500 mg IV weekly in a 28-day cycle in dose escalation. Doses at 1500 and 2000 mg IV biweekly are being explored in dose expansion. The primary endpoint was safety and tolerability. Objective response rate by investigator assessment per RECIST v1.1 of patients with NSCLC treated at 1500 and 2000 mg IV biweekly in three cohorts is reported. Results: As of 26 May 2023, 217 enrolled patients received MCLA-129 in China. The data cut-off was 24 Nov 2023. The most common treatment-emergent adverse events (TEAEs) were infusion related reaction (71.9%), hypoalbuminemia (54.8%), decreased neutrophil count (46.1%), and decreased white blood cell count (40.1%). TEAEs mostly were grade 1-2. Grade ≥3 TEAEs and drug-related TEAEs were reported in 51.6% and 39.2% of patients, respectively. 176 of the 215 NSCLC patients were evaluable. The confirmed objective response rates (ORR) in Cohort A, B and C were 43.5%, 28.6% and 21.8%, respectively. Especially, for patients in Cohort A receive prior MET TKI, the ORR was 37.5% and disease control rate (DCR) was 93.8%. Overall efficacy is shown (Table). Conclusions: MCLA-129 demonstrates robust and durable antitumor activity in patients with NSCLC harboring METex14, EGFR exon20ins and sensitized EGFR mutations, with a manageable safety profile; enrollment in dose expansion is ongoing. Clinical trial information: NCT04930432 . [Table: see text]
Final analysis of SCARLET study: A single-arm, phase II study of sotorasib plus carboplatin-pemetrexed in patients with advanced non-squamous, non-small cell lung cancer KRAS G12C mutation.
Authors: Yoshioka Hiroshige , Akamatsu Hiroaki , Sakata Shinya , Azuma Koichi , Uemura Takehiro , Tsuchiya-Kawano Yuko , Osuga Mitsuo , Koh Yasuhiro , Morita Satoshi , Yamamoto Nobuyuki
Published: June 2024

8616

Background: Efficacy and safety of sotorasib in combination with platinum-doublet chemotherapy in KRAS G12C-mutated non-squamous, non-small cell lung cancer (non-Sq, NSCLC) has been reported with a limited follow-up period. Methods: Efficacy and safety of sotorasib in combination with platinum-doublet chemotherapy in KRAS G12C-mutated non-squamous, non-small cell lung cancer (non-Sq, NSCLC) has been reported with a limited follow-up period. Results: Between Oct 2021 and Jul 2022, 30 patients were enrolled and the median follow-up time was 14.8 months (range, 0.6-21.7). The primary endpoint, ORR by independent review was 88.9% (80%CI 78.5-94.8%, 95%CI 70.8-97.6%). Median PFS was 6.6 months (95%CI 5.3-16.7 months) and PFS rate at 12 months was 37.0%. Median time to treatment failure was 7.9 months (95%CI 5.4-13.9 months). Median OS was 20.6 months (95%CI 8.1 moths - not estimated) and OS rate at 12 months was 66.7%. Similar to the initial report, efficacy did not differ by PD-L1 expression level. In patients with PD-L1 expression level ≥50% / 1-49% / < 1%, ORR was 76.9% / 100.0% / 100.0%, and median PFS was 7.6 / 5.7 / 9.7 months, respectively. Common adverse events were anemia, platelet count decreased, neutrophil count decreased, decreased appetite and nausea. Grade≥3 AEs were mostly hematological toxicities, and one treatment-related death (pneumonia) occurred. Twenty-two plasma samples were collected and analyzed using NGS at the time of disease progression. Of those, an increased allele frequency of KRAS G12C was observed in 73% of the patients. TP53 mutation was detected in 55%, and other resistance mechanisms included CDKN2A, BRAF and PIK3CA mutations. Conclusions: Sotorasib in combination with CBDCA/PEM demonstrated favorable ORR with modest PFS and good tolerability in advanced non-Sq, NSCLC patients with KRAS G12C mutation. Clinical trial information: jRCT2051210086 .
Efficacy of immunotherapy retreatment in patients with non-small cell lung cancer receiving consolidative durvalumab.
Authors: Carroll Allison Baker , Kohler Lindsay Renee , Cipriani Amber Britton , Patel Shetal Arvind , Chen Kevin Yanjun
Published: June 2024

8625

Background: The standard of care for patients with stage III, unresectable non-small cell lung cancer (NSCLC) is curative intent chemoradiation followed by durvalumab consolidation. However, most patients progress necessitating further treatment. Although immunotherapy (IO) is the cornerstone of treatment in advanced/metastatic disease, the benefit in patients who received prior durvalumab is unclear. Clinical trials excluded prior IO exposure and current guidelines do not provide specific recommendations. This study aims to characterize the efficacy of post-durvalumab IO treatment. Methods: This was a retrospective cohort study conducted at the University of North Carolina (UNC) Medical Center. Adult patients with unresectable NSCLC who received chemoradiation and consolidative durvalumab followed by subsequent systemic therapy for disease progression between February 2018 to May 2023 were included. Patients were excluded if they received targeted therapy as subsequent systemic treatment. The primary endpoint was real-world progression-free survival (rwPFS) of post-durvalumab treatment. Key secondary outcomes included physician assessed response, overall survival (OS), and subgroup analyses to identify biomarkers which may predict benefit from IO retreatment. Results: A total of 66 patients met inclusion criteria, of which 39 (59%) received subsequent chemotherapy alone and 27 (41%) received IO-containing therapy. Of those who received IO-containing treatments, 18 received chemotherapy plus IO (chemoIO) and 9 received IO alone. Durvalumab was discontinued for therapy completion (chemotherapy: 18%, IO: 26%), disease progression (chemotherapy: 54%, IO: 48%), or side effects (chemotherapy: 26%, IO: 19%). No significant difference was observed between median rwPFS of chemotherapy versus IO-containing therapy (7.0 months vs 5.8 months, respectively; p = 0.9419) or OS (13.0 months vs 12.6 months, respectively; p = 0.5769). Notably, patients in our cohort who received IO alone had a numerically longer rwPFS compared to chemoIO (12.6 months vs 5.8 months, respectively; p = 0.3951), as well as a numerically longer OS (12.6 months vs 6.4 months, respectively; p = 0.8885). Conclusions: This study found that there were no statistically significant differences in median rwPFS or OS between chemotherapy or IO-based regimens following the conclusion of durvalumab consolidation. Interestingly, we observed a numerically improved rwPFS and OS in those who received IO alone compared to chemoIO, which suggests there may be key clinical or molecular features that may help identify patients who benefit from IO therapy. We acknowledge the limitations of this small, retrospective study. The efficacy of IO-based regimens post-durvalumab warrants further investigation in a larger, prospective manner to assess the risks and benefits of IO retreatment.
High PD-L1 expression among patients with ALK rearranged non–small cell lung cancer and response to first line ALK tyrosine kinase inhibitors.
Authors: Nie Yunan , Staley Alyse , Hinz Trista , Merrick Dan , Yang Michael , Schenk Erin L. , Bunn Paul A. , Camidge David Ross , Heasley Lynn , Patil Tejas
Published: June 2024

8626

Background: Patients with ALK rearrangements are highly responsive to ALK tyrosine kinase inhibitors (TKIs). Negative prognostic markers to ALK TKIs include TP53 alterations and ALK Variants 3a/b. The prognostic role that PD-L1 expression plays in first line ALK TKI outcomes is less clear. Methods: Retrospective review of patients with metastatic ALK-rearranged NSCLC seen between 2015 - 2022 at the University of Colorado who received first line ALK TKIs was performed. PD-L1 expression was denoted as high (≥50%) or low (< 1% or 1-49%) based on pre-treatment biopsies. Clinicopathologic features, treatment outcomes, and genomic data were collected. Survival outcomes were assessed using Kaplan Meier methods. Multivariate modeling adjusted for brain metastases, TP53 mutations, ALK variant status, and ALK TKI. PD-L1 was overexpressed in EML4-ALK murine cell lines with lentiviruses. In vitro and in vivo response to ALK TKIs were compared to non-infected cell lines. Neutrophils and lymphocytes were quantified on pre-treatment H&E slides. Results: Baseline characteristics of 130 patients are shown. Median PFS was significantly (p < 0.001) longer in the PD-L1 low cohort than the PD-L1 high cohort (21 vs 11 mos, HR 0.44, 95% CI 0.29 – 0.66). There was no difference in OS between the PD-L1 low and PD-L1 high cohort (p = 0.4, 107 vs 91 mos, HR 0.86, 95% CI 0.46 – 1.61). In an alectinib sub-group analysis (n = 89), PD-L1 high expressers had a higher rate of CNS progression (93.0 vs 73.9%, p = 0.022). Forced overexpression of PD-L1 in murine EML4-ALK cell lines exerted no difference to in vitroor in vivo response to alectinib. Pre-treatment biopsies from the PD-L1 high cohort (n = 19) revealed significantly more neutrophils (p = 0.021), but not lymphocytes (p = 0.904). Conclusions: High PD-L1 expression (≥50%) is associated with worse PFS and higher intracranial progression rate among those receiving ALK TKIs. Induced PD-L1 expression in ALK cell lines did not alter in vitro or in vivo ALK TKI sensitivity. Higher neutrophil counts track with high PD-L1 expression (≥50%), suggesting that differences within the immune tumor microenvironment may be relevant. [Table: see text]
Clinical-genomic characteristics in patients with EGFR-mutated non-small cell lung cancer harboring MET copy number gains after progression on EGFR-TKI: A report from LC-SCRUM-TRY.
Authors: Hirata Tsuyoshi , Izumi Hiroki , Matsumoto Shingo , Nishino Kazumi , Kato Terufumi , Kodani Masahiro , Chikamori Kenichi , Hosomi Yukio , Hara Satoshi , Kawashima Yosuke , Kuyama Shoichi , Shibata Yuji , Udagawa Hibiki , Sakai Tetsuya , Sugiyama Eri , Nosaki Kaname , Zenke Yoshitaka , Umemura Shigeki , Yoh Kiyotaka , Goto Koichi
Published: June 2024

8628

Background: MET amplification (amp) account for 10-15% of resistance mechanism in EGFR-mutated non-small cell lung cancer (NSCLC) to EGFR-tyrosine kinase inhibitor (TKI) treatment. MET copy number (CN) gains consists of MET focal amp and polysomy (poly), but the clinical characteristics and outcome of EGFR-TKI resistant NSCLC patients harboring MET amp, poly remains unclear. Methods: The clinical-genomic characteristics and treatment outcome ofEGFR-TKI resistant EGFR-mutated NSCLC registered in LC-SCRUM-TRY (UMIN000041957) were analyzed. Genetic resistant alterations were screened using next-generation sequencing (NGS) (Tissue; Oncomine Precision Assay [OPA] or Plasma; Guardant360 [G360]), and MET-fluorescence in-situ hybridization (FISH). MET amp was defined as MET CN ≥4 (OPA), MET CN ≥2.12 (G360) or MET/CEP7 ratio ≥2 (FISH). MET poly was defined as MET CN≥5 and MET/CEP7 ratio <2 by FISH. Results: A total of 1559 patients had been enrolled in LC-SCRUM-TRY between Sep 2020 and Jan 2024. Of 1537 analyzed samples, 666 (43%) were EGFR-TKI resistant samples. Of these, 92 (14%), 239 (36%) and 335 (50%) had MET amp, poly, and no CN gain (no CNG), respectively. Patient characteristics and treatment outcome with 1st line EGFR-TKI and platinum-based chemotherapy (PBC) post EGFR-TKI is summarized (Table 1). The overall response rate (ORR) of PBC post EGFR-TKI in the patients with MET amp, poly and no CNG was 41%, 29% and 31%, respectively (p=0.34), with median progression-free survival (mPFS) being 5.7 months, 6.8 months, and 6.7 months (p=0.02). In addition, 12 and 11 of patients with MET amp and poly were enrolled into clinical trial of MET-targeted therapy (MET-TKI, n=2; MET-antibody-drug conjugate [ADC], n=4; EGFR/MET-antibody, n=2), and MET non-targeted therapy (EGFR-TKI, n=5; other ADCs, n=10: immunotherapy; n=1). The ORR of MET-targeted therapy/MET non-targeted therapy were 60/0% for MET amp, and 0/33% for MET poly, respectively. Conclusions: Patients with shorter PFS with prior 1st line EGFR-TKI are more likely to have MET amp. The efficacy of standard PBC post EGFR-TKI in patients with MET CNG is limited. Current MET-targeted therapy may not be effective for EGFR-mutated NSCLC harboring MET poly after progression on EGFR-TKI. [Table: see text]
Preliminary results from a FIH, open-label phase 1 study with BMC128, a rationally designed live bacterial consortium, in combination with nivolumab.
Authors: Perets Ruth , Meshner Shiri , Tirosh Osnat , Eshar Shiri , Metz-Breiner Alona , Kruger Ben-Shabat Sheerli , Ben-Yehuda Hila , Haber Elran , Cohen-Asis Meital , Maurice-Dror Corinne , Ringel Yehuda , Holland Roy , Shirman Yelena , Shentzer kutiel Talia
Published: June 2024

8631

Background: Immune-Checkpoint inhibitors (ICI) have transformed the treatment of solid tumors, specifically in cutaneous melanoma, clear cell renal cell carcinoma (ccRCC) and non-small cell lung cancer (NSCLC). Despite these advances, resistance to ICI eventually occurs in many patients. Recent reports have found that patients showing poor response to ICI are characterized by a reduced gut microbiome diversity, suggesting that the gut microbiome might affect immune activation by ICI. BMC128 is a live bacterial consortium of 4 bacterial strains designed to induce anti-tumor immune function when given in conjunction with ICI. These strains were identified by analyzing microbiome data obtained from NSCLC and ccRCC patients presenting varied responses to ICI, using a proprietary computational discovery platform enabling high-resolution functional microbiome analysis. In pre-clinical studies, treatment with BMC128 potentiated the efficacy of ICI in breast cancer and melanoma mouse models, reducing tumor volume, increasing the number of responders, and demonstrating an increase in infiltrating immunocytes: CD4, CD8 and NK cells. The aim of this study was to assess the safety and tolerability of BMC128 in combination with nivolumab. Methods: 12 patients with ccRCC, cutaneous melanoma and NSCLC-adenocarcinoma (EGFR/ALK wild-type) (6, 1 and 5 patients, respectively), who previously progressed on PD1/PDL-1 inhibitors were recruited to this FIH open label phase 1 study. Patients were treated with a daily oral dose of BMC128 4*108 live cells/ strain in combination with nivolumab 480mg q4weeks. The study treatment consisted of 4 stages: depletion with antibiotics, induction with BMC128 monotherapy, combination treatment, and nivolumab monotherapy. Results: No SAEs related to BMC128 were reported throughout the duration of the study. Two patients exhibited minor AEs that were potentially associated with BMC128. At the current time point, 4 out ofthe first 8 patients in the study showed SD and sustained benefit beyond the first imaging timepoint, following the combination treatment. Altogether demonstrating clinical benefit for a total of 16 weeks (2 patients), 24 weeks (1 patient), and 68 weeks (1 patient). Conclusions: BMC128 has demonstrated an excellent safety profile and preliminary beneficial clinical effect. A phase 2 study to investigate the efficacy of BMC128 is planned to be initiated in late 2024. Clinical trial information: NCT05354102 .
Safety and efficacy of osimertinib in patients with NSCLC and uncommon tumoral EGFR mutations: A systematic review and meta-analysis.
Authors: N. Priantti Jonathan , Vilbert Maysa , Moraes Francisco Cezar A , Michelon Isabella , Castro Caio , Leighl Natasha B. , Cavalcante Ludimila , Fujiwara Yu , Addeo Alfredo , Bar Jair , Cortellini Alessio , Nassar Amin , Naqash Abdul Rafeh
Published: June 2024

8642

Background: Osimertinib is broadly used for advanced EGFR-mutant NSCLC patients. However, the activity of osimertinib is not fully characterized in tumors harboring uncommon EGFR mutations, which represents about 10% of EGFR-mutated NSCLC cases. Hence, we conducted a systematic review and meta-analysis to assess the efficacy and safety of osimertinib in patients with NSCLC and uncommon tumoral EGFR mutations. Methods: PubMed, Embase, and the Cochrane Library were searched for eligible studies. Uncommon EGFR mutations were defined as any mutation other than the exon 19 deletion, L858R and T790M mutations, and exon 20 insertion, except when in compound. Efficacy was assessed by objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Heterogeneity was examined with I2 statistics and random-effect model was used for a meta-analysis. Results: Nine studies comprising 331 patients were included. Median follow-up ranged from 12.6 to 22.0 months (mos). Median age in each study ranged from 51 to 72 years old (table). Overall, 62% (205/331) of patients were female and 77% (256/331) of patients had an ECOG PS ≤1. About 78% (258/331) of patients received Osimertinib in a 1st line setting. Uncommon tumoral EGFR mutations included G719X in 40% (131/331) of patients, L861X in 27% (91/331), and S768I in 15% (49/331). Pooled analysis showed an overall ORR of 49.5% (95% CI, 42.2 – 56.9), a DCR of 90.2% (95% CI, 86.2 – 94.3), a median OS of 24.5 mos (95% CI, 11.9 – 24.5), a median PFS of 9.5 mos (95% CI, 8.2 – 11.0), and a median DOR of 17.4 mos (95% CI, 7.9 – 22.7). Intracranial (i) efficacy had an iORR of 50.3% (95% CI, 30.3 – 70.3), an iDCR of 92.8% (95% CI, 76.2 – 100), and a median iPFS of 6.1 mos (95% CI, 4.5 – 6.6). In a subgroup analysis according to EGFR mutation, overall ORR was significantly different in patients with tumoral G719X, S768I and L861 mutations (ORRs of 28.8%, 33.3%, and 67.7%, respectively, p for subgroup differences < 0.01). Overall, osimertinib was well tolerated with a frequency of all-grade AEs of 86.2% (95% CI, 61.2 – 100) and ≥ G3 of 18.0% (95% CI, 1.2 – 34.7). Conclusions: This systematic review and meta-analysis suggests that patients with NSCLC with uncommon tumoral EGFR mutations may benefit from osimertinib treatment. Patients harboring tumoral L861 mutation achieved a significantly higher ORR compared to the modest ORR in G719X, S768I cases. [Table: see text]
Hematology/oncology clinical investigator training: Is current model of education adequate?
Authors: Shergill Ardaman , Cahill Kirk , Major Ajay , Patel Anand Ashwin , Cohen Kenneth Stuart , O'Donnell Peter H.
Published: June 2024

9005

Background: Clinical investigator training (CIT) is commonly performed in an apprenticeship manner rather than following a prospective education model. This may lead to disparities in educational prospects. There is greater accesiblity for training opportunites prevailing in larger academic institutions – an advantage not always within reach for majority of oncology patients and professionals. Lack of predefined standard competencies during fellowship training may lead to significant heterogeneity, weaken the current pipeline, and decrease the number of principal investigators (PIs) for clinical trials. We performed a national needs assessment to understand oncology trainee and faculty perceptions of CIT. Methods: Program directors and leaders at 102 U.S. hematology/oncology (hem/onc) fellowship programs were contacted via email to invite their respective trainees and faculty to answer a 32-question cross-sectional survey. The study was IRB excempt. The survey was developed with the University of Chicago Survey Lab. Four thematic areas were interrogated: current level of experience in CI, knowledge of PI roles and responsibilities (R/R), areas of perceived weakness/lack of confidence related to CI, and interest in a course that teaches CI. Response frequencies and descriptive statistics were analyzed, with the goal of informing future targeted educational initiatives. Results: 207 respondents from 47/102 (46%) institutions completed the survey between 5/2023 – 11/2023. Respondents included 92 (40%) trainees and 137 (60%) attendings, 47% were men, 47% women and 57% had more than 9 years of experience as an attending post-speciality training. Among attendings, only 4.4% reported never participating in CIT, compared to 55.4% of trainees. Informal or “on the job” teaching was the most common method of learning PI R/R with response rate of 58% in attendings and 62% in trainees. Trainees reported lack of confidence and need for education in all aspects of CIT, and 85% indicated high level of interest in enrolling in a CIT course. Most attendings reported lack of confidence in areas of budget development (57%), quality of life (70%) and translational correlatives (51%). Others reported feeling weaknesses in designing primary and secondary end points (32%), letter of intent writing (33%) and creating protocols (31%). 53% of the attendings were interested in enrolling in a CIT course. Conclusions: To our knowledge, this is the first reported survey formally assessing current perceptions of preparedness in CIT within hem/onc in the U.S. Our findings strongly indicate that CIT educational gaps exist, even for attendings with prior CIT experience, and that training deficits are marked for trainees. A structured, practical, and widely-accessible CIT program is urgently needed to prepare the future hem/onc workforce. Acknowledgement: MERITS program and Section of Hem/Onc at University of Chicago.
Artful oncology: A comprehensive psychosocial oncology curriculum for hematology/oncology fellows.
Authors: Al-Mondhiry Jafar , Walker Kimberly Lowery , Bires Jennifer , Caulkins Leigh Ann , Hughes Cheryl , Mohess Denise , Wadlow Raymond Couric
Published: June 2024

9008

Background: Of patients with cancer, 46% experience significant psychosocial distress, a factor linked to higher morbidity, mortality and costs of care. Oncologists themselves face psychosocial distress, particularly during their fellowship training, with as many as 38% of hematology/oncology (H/O) fellows reporting burnout during training. The ACGME recognizes this risk and has recently included well-being skills in their professional milestones, in addition to milestones for assessing psychosocial issues and communication skills for addressing these complex patient needs, which are often a source of distress among clinicians. Very few published curricula are available to address these layered learning needs among H/O fellows. Methods: “Artful Oncology” is a multifaceted curriculum for H/O fellows focusing on four pillars: 1) monthly didactic lectures about psychosocial issues within cancer care; 2) bimonthly narrative medicine seminars reflecting on didactic themes; 3) quarterly communication skills training conducted with standardized patients; and 4) monthly cancer survivorship support group facilitation. This curriculum was instituted with the inaugural class of H/O fellows at Inova Schar Cancer Institute in 2021 (total 6 fellows to date) with iterative improvements. Outcomes were measured through self-assessed communication skills, scored feedback for each didactic, annual Physician Belief Scale (PBS) surveys, quarterly Professional Quality of Life (ProQOL)-Health and abbreviated Maslach Burnout Inventory (MBI) surveys. Results: Fellows rated didactics as being relevant to their work, prepared to implement the skills learned into clinical practice, and would recommend these sessions to others (average 4.58, 4.59, and 4.67 out of 5-point Likert scale). Among 19 evaluated didactic topics evaluated to date, the most highly rated sessions included Oncology Psychiatry, Integrative Approaches to Symptom Management, Hospice Behind the Scenes, and Moral Injury/Moral Distress (average 5.0); lowest rated included Mindfulness, Sexual Health, Recognizing Depression, Grief, and Adolescents/Young Adults (average 4.29). PBS scores numerically improved from 2022 to 2023 (78 to 68.8 out of 160, lower being associated with a more psychosocial approach to patient care). MBI and ProQOL Health scores were largely unchanged (<2 point difference on average). Self-assessed communication skills averaged across rising fellows increased from 4.38 to 7.44 out of 10 between 2022 and 2023. Conclusions: The Artful Oncology curriculum numerically improved self-assessed communication skills and attitudes regarding the physician role within psychosocial aspects of patient care. Didactic sessions were rated as highly relevant, actionable, and recommended by H/O fellows. Study of this curriculum over a longer timeframe with larger numbers of fellows is ongoing to better evaluate effects.
Improving goal concordant care clinician workshops: Do patients benefit?
Authors: Bitar Heather Nicole , Dale William , Razavi Marianne , Liou Eleana , Shaikh Mohammad Zameer Zameer , Morse Denise , Jun Christine , Mecusker Eric , Ramirez Carey , Leitner Andrew , Artz Andrew S. , Waisman James Ross , Buga Sorin , Clark Karen L. , Zachariah Finly
Published: June 2024

9035

Background: From 2020-2023, the Alliance of Dedicated Cancer Centers (ADCC) undertook a national initiative to improve goal concordant care (IGCC) where all cancer patients and their families receive care that aligns with their values and priorities. One of the core components of the program was to implement a formal communications skills training program supporting the delivery of goal concordant care. As an ADCC member, City of Hope’s (COH) Department of Supportive Care Medicine created the Improving Goal Concordant Care Virtual Workshop Series to address this need. Methods: The 2-part workshop series covered: Goal concordant care, having difficult conversations, advanced care planning (ACP), advance directives, Physician Orders for Life Sustaining Treatment forms, and code status. Physicians and nurse practitioners (NPs) were independently evaluated regarding their quality of care pre-/post workshop #1 by their outpatients through the “Heard and Understood (HAU)” survey, a patient-reported quality measure with 4 items: I felt heard and understood (HU), Provider understood what was important my life (UL), Provider saw me as a person (SP), Provider put my best interests first (BI). Response categories ranged from 1, not at all trueto 5, completely true. Top-box rates and percentage of patients responding completely true for a given item were calculated for each clinician. Pre-/post changes in top-box rates were examined with paired t-tests. Differences in rates over time, by clinician type, were evaluated using mixed effect modeling. Survey items were initially analyzed individually, then combined. A p-value < 0.05 was considered statistically significant. Results: A total of 37 clinicians (26 Physicians and 11 NPs) were evaluated. Patients’ experience with physicians (NPs excluded) improved between pre/post training: The rates increased for the overall HAU scale (4.31, p=0.002), as well as for several individual items such as HU, UL and BI (5.24, 6.33 and 2.52 respectively, p-values<0.05). Notably, the rates for HU increased for physicians but not for NPs (5.24 vs -3.22, difference= 8.46, p=0.012), though NPs had a higher top-box rate at baseline compared to physicians (90.74 vs 78.04, p<0.001). Between group rate differences were not significant for the overall HAU scale over time. Conclusions: Patients’ experience with hematology and oncology physicians improved after physicians received IGCC communication skills training. Moreover, the patients’ experience with NPs was rated higher than physicians before training, but there were no significant differences after training. To further improve physician-patient communication regarding ACP and goal concordant care, the program will adapt and expand to additional departments throughout the COH clinical network.