bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 2 clinical trial of the proautophagic drug ABTL0812 combined with paclitaxel and carboplatin in first-line patients with advanced squamous non-small cell lung carcinoma.
Authors: Bosch-Barrera Joaquim , Moran Teresa , Estévez-García Purificación , Martín-Martorell Paloma , Sabatier Renaud , Nadal Ernest , Lizcano Jose M. , Pedrós-Gámez Oriol , Pérez-Montoyo Héctor , Yeste-Velasco Marc , Domenech Carles , Alfon Jose Alberto 
Published: June 2023

9059 Background: ABTL0812 induces the inhibition of Akt/mTOR pathway by upregulation of TRIB3 protein, an endogenous Akt inhibitor, and promotes endoplasmic reticulum (ER) stress. As a result, ABTL0812 induces cytotoxic autophagy that leads to specific death of cancer cells, without affecting non-tumor cell viability. A Phase II clinical trial was designed where ABTL0812 was evaluated in combination with paclitaxel and carboplatin in first-line patients with advanced squamous non-small cell lung cancer (NSCLC). Methods: ABTL0812 was administered 1300 mg TID orally with 175 mg/m2 paclitaxel and AUC5 carboplatin every 3 weeks, for up to 8 cycles, followed by ABTL0812 as a maintenance until disease progression or unacceptable toxicity. The study enrolled patients with non-irradiable IIIb stage or stage IV squamous NSCLC. Primary endpoint was overall response rate (ORR) by RECIST criteria v.1.1. Secondary endpoints were progression free survival (PFS), overall survival (OS), duration of response (DOR), safety and tolerability according to CTCAE v4.03, pharmacokinetics (PK) of ABTL0812 enantiomers ((-)-ABTL and (+)-ABTL) and pharmacodynamics assessed by two surrogate blood biomarkers: TRIB3 and CHOP. Results: Forty patients were included; median age was 66.1 years old; 90% men/10% women; 100% ECOG 0-1; 30% current smokers/67.5% former smokers and 37.5% had received prior chemotherapy > 12 months before inclusion. 39 patients had at least 1 adverse event (AE), anemia appeared in 32.5% of the patients (5.0% grade 3), neutropenia in 27.5% (25% grades 3-4) and thrombocytopenia in 17.5% of the patients (2.5% grade 3). For non-hematological AEs, asthenia was reported in 62.5% of the patients (2.5% grade 3); diarrhea in 45% (no grade 3-4) and nausea in 37.5% (5% grades 3-4). Twenty-five patients reach the primary endpoint for efficacy evaluation. ORR was 52.0% (95% CI 34.2-65.9) and 32.0% of the patients had stable disease. Median OS was 22.5 months (10.4-NC), median progression free survival 6.2 months (4.4-8.8), and DOR 5.1 months (3.9-7.4). Area under the curve (µg·h/ml) for (-)-ABTL and (+)-ABTL were 39.0±12.3 and 17.1±6.3 respectively, maximal concentrations (µg/ml) were 6.4±2.6 and 5.1±2.2 and minimum concentrations (µg/ml) 2.2±1.5 and 0.8±1.3. TRIB3 and CHOP PD biomarkers were induced by the treatment. Conclusions: The combination of ABTL0812 with paclitaxel and carboplatin shows survival outcomes that compare favorably with historical controls in squamous-NSCLC with an acceptable safety profile. PK analysis is compatible with drug activity, and pharmacodynamic analysis shows drug engagement. Clinical trial information: NCT03366480 .
Emerging phase 1 data of BLU-451 in advanced NSCLC with EGFR exon 20 insertions.
Authors: Nguyen Danny , Shum Elaine , Baik Christina S , Janne Pasi A. , Patel Jyoti D. , Schenk Erin Lynn , Shibata Yuji , Yu Helena Alexandra , Albayya Faris , Pearson Paul , Feng Minjie , Louie-Gao Melinda , Zalutskaya Alena , Spira Alexander I. 
Published: June 2023

9064 Background: In patients (pts) with NSCLC harboring EGFR exon 20 insertions (ex20ins), treatment options are limited, with platinum-based chemotherapy with/without programmed death-ligand 1 inhibitors being the standard of care in first line, and recent accelerated approvals of mobocertinib and amivantamab in the USA for second-line treatment. These second-line therapies have overall response rates of 28% and 40%, respectively, limited CNS activity, and are associated with AEs such as severe gastrointestinal AEs and edema. BLU-451 is an investigational, CNS-penetrant, potent, selective, and wild-type sparing EGFR tyrosine kinase inhibitor that is under investigation in the ongoing phase 1/2 CONCERTO trial (NCT05241873), including in pts with ex20ins. Methods: In phase 1 dose escalation using a 3+3 design, BLU-451 monotherapy was administered orally QD or BID and given in continuous 21-day cycles. The primary objectives include maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) determinations and safety. Key secondary objectives include antitumor activity, PK, and pharmacodynamics. Pts with EGFR ex20ins–positive NSCLC after prior platinum-based chemotherapy were enrolled. Prior ex20ins–targeted therapy and asymptomatic CNS disease were permitted. Tumor response was assessed per RECIST v1.1. Serial blood samples for analysis of BLU-451 PK and circulating tumor DNA (ctDNA) were collected. Results: As of Jan 20, 2023, 28 pts have been enrolled and dosed in 5 cohorts (100 mg–400 mg QD and 200 mg BID), including 19 (68%) pts with exon 20 insertions. The median number of prior systemic lines of therapy was 2.5 (range, 1–10), and 19/28 (68%) pts had prior ex20ins-targeted agents. The most common AEs were diarrhea (21%), cough (18%), fatigue (14%), pruritis (14%) and rash (14%); all were Grade 1 or 2. There were no dose-limiting toxicities. Partial responses, including a disappearance of a CNS target lesion, were seen, and early evidence of on-target activity with ctDNA reductions was observed. Conclusions: As of the data cutoff, BLU-451 monotherapy was generally well tolerated, with early evidence of clinical activity in heavily pretreated pts with EGFR ex20ins–positive NSCLC. Early data at initial dose levels consisted of tumor reduction including responses, CNS activity, and ctDNA responses. The dose escalation is ongoing to determine the MTD and/or RP2D. Clinical trial information: NCT05241873 .
Efficacy and safety of PD-1/PD-L1 inhibitor plus platinum-based chemotherapy vs. platinum-based chemotherapy alone in patients with previously untreated advanced large-cell neuroendocrine cancer of the lung.
Authors: Mu Fengchun , Fan Bingjie , Li Haoqian , Dong Taotao , Yao Yueyuan , Li Butuo , Jiang Chao , Wang Linlin 
Published: June 2023

9066 Background: Large-cell neuroendocrine carcinoma (LCNEC) is a rare tumor with a poor prognosis and limited treatment options. The efficacy of first-line therapies for LCNEC has not yet been established. This study evaluated the efficacy and safety of the combination of PD-1/PD-L1 inhibitor and platinum-based chemotherapy in treatment-naïve patients with advanced LCNEC. Methods: We retrospectively analyzed patients with advanced LCNEC who were treated with a PD-1/PD-L1 inhibitor plus platinum-based chemotherapy (PD-1/PD-L1 inhibitor group) or with platinum-based chemotherapy alone (chemotherapy group) based on data obtained from electronic databases of three participating cancer centers from January 2015 to August 2022. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) were evaluated for each group. Safety was assessed in all patients who received at least one dose of their assigned treatment. Results: Among the 75 enrolled patients, 25 were allocated to receive PD-1/PD-L1 inhibitor plus platinum-based chemotherapy and 50 were allocated to receive platinum-based chemotherapy alone (patients were matched 1:2 on baseline characteristics). The median PFS was 15.1 months (95% confidence interval [CI], 7.1–23.2) in the PD-1/PD-L1 inhibitor group and 5.3 months (95% CI, 4.4–6.2) in the chemotherapy group (hazard ratio [HR], 0.26; 95% CI, 0.113–0.428; p < 0.0001). The 12-month OS was 88.0% (95% CI, 67.7–96.9) in the PD-1/PD-L1 inhibitor group and 56.0% (95% CI, 41.4–69.7) in the chemotherapy group ( p = 0.0056). The ORRs in the two groups were 40% and 16%, respectively ( p = 0.022), and the DCRs were 96% and 70%, respectively ( p = 0.010). Regarding safety, the most common incidences of grade ≥ 3 adverse events involved neutropenia, leukopenia, anemia, and fatigue. There were no significant differences between the two groups. Immune-related adverse events (irAEs) in the PD-1/PD-L1 inhibitor group included cutaneous hemangiomas, hypothyroidism, anaphylaxis, and pneumonitis. Grade 3 or 4 irAEs were not observed. No new safety signals were noted. Conclusions: First-line PD-1/PD-L1 inhibitor plus platinum-based chemotherapy significantly improved PFS in patients with advanced LCNEC compared with platinum-based chemotherapy alone.
Nivolumab (Nivo) plus ipilimumab (Ipi) 6-month treatment versus continuation in patients with advanced non-small-cell-lung cancer (aNSCLC): 3-year results of the IFCT-1701 DICIPLE phase 3 trial.
Authors: Zalcman Gerard , Madroszyk Anne , Dayen Charles , Molinier Olivier , Egenod Thomas , Debieuvre Didier , Beaucaire-Danel Sophie , Dixmier Adrien , Pichon Eric , Galland-Girodet Sigolène , Giroux Leprieur Etienne , Cloarec Nicolas , Cadranel Jacques , Otto Josiane , Poté Nicolas , Langlais Alexandra , Morin Franck , Antoine Martine , Westeel Virginie , Toffart Anne-Claire 
Published: June 2023

9068 Background: 1st-line immunotherapy (io) is a standard treatment for patients (pts) with advanced NSCLC devoid of targetable mutation. Classical 2-year io duration does not rely on indubitable evidence. We aimed to assess whether 6-month nivo/ipi was equivalent to continuation until progression or unacceptable toxicity in pts with disease control (DC). Methods: In this multicenter non-inferiority randomized phase 3 trial, eligible treatment-naive pts, age>18, PS 0-1, had stage IV NSCLC and measurable disease. They received Nivo 3 mg/kg q2w plus Ipi 1 mg/kg q6w, until progression or unacceptable toxicity for a maximum of 6-month induction treatment. At 6 months, pts with DC and no severe TRAEs were randomized (1:1) into io continuation (arm A), and observation (arm B). At progression, arm A pts received an investigator's choice 2nd line platinum-based chemo, while arm B pts resumed double io. Primary endpoint was progression-free survival (PFS). 450 pts x 2 were to be randomized, to achieve 80% power, with 0.025 one-sided a error. Observing that European filing for the io combo was not submitted, the trial's steering committee recommended to stop the accrual on Jan. 2021. Results: From May. 2018 to Jan. 2021, 265 pts (70.6% male, 62.7yr median age, 59% stage IVB, 22.3% SCC, 9.9% PDL1≥50%, 12.2% PDL1<1%) were accrued. 138 (72.6%) pts had disease progression before 6 months, 11 died (5.8%), 30 (15.8%) experienced TRAEs contra-indicating continuation, 11 (5.8%) were deemed ineligible for randomization. 71 pts with DC were randomized. With a median follow-up from randomization of 29.9 months, median PFS was 20.5 (7.4-36.7) months in arm A, 35.2 (21.4-NR) in arm B. 12-month PFS was 55.6% (38.0-69.9) and 81.2% (62.9-91.1), respectively (p=0.08). Adj.HR (arm B vs. arm A) was 0.66, 95%CI (0.28-1.31), p=0.23. OS data, yet immature, did not show any significant difference between both arms (adj.HR arm B vs. A: 0.54 95%CI (0.20-1.49), p=0.23). From randomization, 28.6% G3-5 TRAEs in arm A were observed vs. 2.9% in arm B (p=0.005). Conclusions: The 6-month i.o. interruption for NSCLC patients with DC did not yield significant PFS or OS differences in this prematurely halted trial. Updated OS with a 3-year follow-up, quality of life and biomarker data, will be presented at the meeting. Clinical trial information: NCT03469960 .
Spectrum of acquired KRAS mutations in driver mutation-positive non-small cell lung cancer.
Authors: Reuss Joshua E. , Gandhi Nishant , Walker Phillip , Nieva Jorge J. , Bustamante Alvarez Jean Gabriel , Carlisle Jennifer W , Desai Aakash , Vanderwalde Ari M. , Ma Patrick C. , Liu Stephen V. 
Published: June 2023

9069 Background: With the emergence of effective targeted-therapies for KRAS G12C, and the development of promising agents for KRAS G12V and G12D among others, the identity of unique KRAS mutations in non-small cell lung cancer (NSCLC) has become increasingly relevant. Acquired KRAS mutations are a known mechanism of resistance observed across driver mutation-positive (DM+) NSCLC. The incidence and diversity of these acquired alterations, and whether they differ from those observed in de novo KRAS-mutated NSCLC, is unknown. Methods: NSCLC molecular profiles were obtained using next-generation sequencing (Caris Life Sciences) with paired whole-transcriptomic sequencing (Illumina NovaSeq) and immunohistochemistry (Caris Life Sciences). Demographic data were abstracted from medical records. KRAS mutation diversity was defined for de novo KRAS-mutated ( KRASmt) NSCLC ( KRAS as only identified driver – KRASmt_dn) and DM+ NSCLC with acquired KRAS mutations (concurrent KRASmt with other known driver – KRASmt_acq). Fisher’s exact test was used to compare the distribution of unique KRAS mutations between the groups. Due to the unique biology of NSCLC with class II/III BRAF mutations, this subset was removed from the KRASmt_acq subgroup for the final analysis. Results: A total of 5932 KRASmt NSCLC samples were identified, among which 5879 were KRASmt_dn and 53 were KRASmt_acq (see table). The distribution of unique KRAS mutations was not significantly different between groups (p = 0.14). Within the KRASmt_dn group, KRAS G12C was most common (40%), followed by G12V (19%), G12D (14%), G12A (7%) and Q61H/G13C (4% each). In the KRASmt_acq group, KRAS G12C was most common (30%), followed by G12D (19%), G12V (17%), Q61H (11%), G12A (7%), and G13C (6%). The most common observed driver mutations in the KRASmt_acq group were EGFR (38%) and MET (30%). In the EGFR group, KRAS G12D (25%), Q61H/G12C (20% each), G12V/G13C (10% each), and G12F/A/R (5% each) were observed. In the MET group, KRAS G12C (25%), G12D/V/A (19% each), Q61H (12%) and G12S (6%) were seen. Among 7 patients with a documented history of smoking in the KRASmt_acq group, KRAS G12D and Q61H were most common (29% each), followed by G12V/F and G13C (14% each). Conclusions: While the distribution of unique KRAS mutations did not differ significantly between KRASmt_dn and KRASmt_acq groups, acquired KRAS mutations were seen across DM+ NSCLC subsets, among which the frequency of observed mutations appeared to vary. The functional and immunological significance of these mutations, and their impact on clinical outcomes, warrants further investigation. [Table: see text]
Outcomes of patients with advanced EGFR mutant lung cancer treated with first line (1L) osimertinib (osi) who would not have met eligibility criteria for the FLAURA trial.
Authors: Wells Connor , Mullin Monica , Sun Sophie 
Published: June 2023

9072 Background: Osi is a 1L therapy for EGFR mutant lung cancer based on the results of the FLAURA clinical trial. Patients on clinical trial are typically highly selected and the overall effectiveness of therapies may be lower in the real-world setting. We report the real-world outcomes of patients treated with first line osi and compare the outcomes of trial eligible and ineligible patients. Methods: Pharmacy records from January 2020 to October 2022 were used to retrospectively identify patients who received 1L osi for advanced EGFR mutant (exon 19 del. or exon 21 L858R) lung cancer in British Columbia, Canada. Patients were deemed ineligible for the FLAURA trial if they met one of five criteria: ECOG ³2, unstable brain metastases (symptomatic or on steroids), hemoglobin <90, platelet <100, or creatinine clearance <50. Comparisons of overall survival (OS) and time to treatment discontinuation (TTD) were made between using Kaplan-Meier survival curves and log-rank testing. Hazard ratios (HR) are reported using Cox regression adjusting for baseline factors (Table). Results: Of 312 patients included, 133 (43%) were considered FLAURA-ineligible. Reasons for ineligibility were poor ECOG (n=120 [including ECOG 2=69, ECOG 3=48, and ECOG 4=4]), unstable brain metastases (n=21), anemia (n=7), thrombocytopenia (n=5), and low creatinine clearance (n=9). Median follow up was 22.7 months. At the time of analysis, 103/133 (77%) of ineligible patients had discontinued osi and 87/133 (65%) had died. 82/179 (45%) of eligible patients had discontinued osi and 53/179 (30%) were deceased. The median TTD in the ineligible group was 11.9 months (95% CI 10.5-15.5) vs 26.9 months (95% CI 21.9- 34.6) in the eligible group (p<0.001), HR 2.1 (95% CI 1.5-2.9, p<0.001). The median OS in the ineligible group was 15.8 months (95% CI 12.4 to 21.1) vs NR [not reached] (95%CI 28.5 to NR) in the eligible group (p<0.001), HR 2.6 (95% CI 1.8-3.7, p<0.001). Rates of dose reduction for toxicity were similar between ineligible (25%) and eligible (19%) patients (p=0.25). Second-line therapy was received by 28/102 (27%) of trial ineligible patients and 46/82 (56%) of trial eligible patients. Conclusions: Over 40% of the real-world population receiving 1L osi would have been ineligible for the FLAURA clinical trial. These patients had significantly inferior outcomes. This study provides benchmark data to better inform patient prognosis using real-world data. [Table: see text]
Integrated efficacy and safety of brigatinib in patients with ALK TKI-naive advanced ALK+ NSCLC in the ALTA-1L and J-ALTA studies.
Authors: Camidge D. Ross , Sugawara Shunichi , Kondo Masashi , Kim Hye Ryun , Ahn Myung-Ju , Yang James Chih-Hsin , Han Ji-Youn , Hochmair Maximilian J. , Lee Ki Hyeong , Delmonte Angelo , Kudou Kentarou , Asato Takayuki , Liu Yuyin , Vranceanu Florin , Fram Robert J. , Ohe Yuichiro , Popat Sanjay 
Published: June 2023

9078 Background: Brigatinib demonstrated efficacy and manageable safety in patients (pts) with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI)-naive ALK+ non-small cell lung cancer (NSCLC) in phase 3 (ALTA-1L) and phase 2 (J-ALTA) trials. We present results of integrated efficacy and safety analyses of ALTA-1L and J-ALTA. Methods: ALTA-1L (NCT02737501) and J-ALTA (NCT03410108; conducted in Japan) were open-label, multicenter studies in pts with advanced or metastatic ALK+ NSCLC. Pts in ALTA-1L and in part 3 of J-ALTA were ALK TKI-naive. Stable or asymptomatic brain metastases were allowed in both studies. Pts received brigatinib 180 mg qd (7-day lead-in at 90 mg). Primary endpoints were blinded independent review committee (IRC)-assessed progression-free survival (PFS) in ALTA-1L and IRC-assessed 12-month PFS in the J-ALTA ALK TKI-naive cohort (both per RECIST v 1.1). Secondary endpoints included IRC-assessed objective response rate (ORR), duration of response, intracranial ORR, intracranial PFS, overall survival, and safety. Pooled efficacy and safety data from both studies are presented. Results: The pooled analysis population included 169 pts (ALTA-1L, N = 137; J-ALTA ALK TKI-naive cohort, N = 32). Median follow-up overall was 35.8 months (last pt last contact: ALTA-1L, January 2021; J-ALTA, July 2021). Most (66%) pts were aged < 65 years, 24% had baseline brain metastases, 95% had stage IV disease at study entry, and 21% had received prior chemotherapy for locally advanced or metastatic disease. With brigatinib treatment, median PFS by IRC was 29.3 months (95% CI, 23.9‒44.7). The confirmed ORR was 79% (95% CI, 72‒85%), with 36 complete responses and 97 partial responses. Median duration of response was 38.1 months (95% CI, 22.9‒not reached). Median overall survival was not reached; the 3-year survival rate was 74% (95% CI: 66‒80%; 84 pts at risk). Intracranial ORR and intracranial PFS will be presented. Grade 3/4 treatment-emergent adverse events were reported in 74% of pts; the most common were increased blood creatine phosphokinase (31%), hypertension (18%), and increased lipase (16%). Any grade interstitial lung disease/pneumonitis was reported in 12 (7%) of pts. Adverse events led to treatment discontinuation in 11% of pts. Conclusions: Brigatinib treatment demonstrated clinically meaningful systemic and intracranial efficacy in this integrated analysis of pts with ALK TKI-naive advanced or metastatic ALK+ NSCLC in the ALTA-1L or J-ALTA trials. Safety results were consistent with the known profile for brigatinib, with no new safety findings. Clinical trial information: NCT02737501 ; NCT03410108 .
Survival associations and driver oncogene overlap for copy-number amplifications of ERBB2, KRAS and MET in non-small cell lung cancer.
Authors: Watson Alexander , Krause Harris Benjamin , Elliott Andrew , Farrell Alex Patrick , Liu Stephen V. , Ma Patrick C. , Vanderwalde Ari M. , Sledge George W. , Spetzler David , Schenk Erin Lynn , Camidge D. Ross 
Published: June 2023

9084 Background: Next-generation sequencing (NGS) to detect targetable oncogenic driver mutations is standard of care in non-small cell lung cancer (NSCLC). However, the interpretation and clinical impact of copy number amplifications (CNA) of driver genes is less clear. ERBB2, KRAS and MET are oncogenic drivers with intersecting resistance mechanisms and evolving therapeutic landscapes. We examined the overlap between other oncogenic drivers and CNA of these genes, and the association of CNA with overall survival (OS), in a cohort of patients with NSCLC. Methods: NGS of DNA (592 genes or WES)/RNA (WTS) was performed for 5870 consecutive lung adenocarcinoma tumors submitted to Caris Life Sciences (Phoenix, AZ). The copy number of each exon was determined by calculating the average depth of the sample along with the sequencing depth of each exon. Driver oncogenes (Driver+/-) were defined as pathogenic fusions in ALK, NTRK (1,2 and 3), RET and ROS1 or pathogenic SNVs/indels in ALK, BRAF, EGFR, ERBB2, KRAS, MET. Tumor mutational burden high (TMB-H) was defined as 10 mutations per MB. The χ² test was applied as appropriate ( p < .05). Results: The cohort was 55% female; median age was 69 years (range 24-89) and similar across all cohorts. Incidence of CNA at different amplification thresholds was correlated with oncogene drivers. At CNA ≥6 for ERBB2 and KRAS, but CNA ≥4 for MET, a significant tendency for mutual exclusivity with driver mutations was observed (log2 odds ratio ERBB2: -3.1, KRAS: -1.1 , MET: -2.2 , all p < .001). Tumors meeting these thresholds were designated CNA-High ( Gene-H), versus CNA-Low ( Gene-L). Only one tumor harboured two CNA-H genes ( KRAS and MET). Independent of CNA status, the TMB-H frequency was decreased in Driver+ tumors (27% vs 52% in Driver-, p < .001). CNA-H tumors were associated with decreased OS (compared to CNA-L); for ERBB2-H, hazard ratio (HR) 1.74 (95% CI 1.44-2.10, p < .001), for KRAS-H HR 1.29 (1.16-1.65, p < .001), and for MET-H HR 1.46 (1.28-1.68, p < .001). Similar results were observed when stratified by driver mutation status (Table), with the exception of KRAS/Driver- tumors. Conclusions: These data suggest tumors with high CNA of ERBB2, KRAS and MET represent clinically distinct entities and are significantly less likely to harbour concurrent driver oncogenes. The association between increased copy number and worse OS suggests amplified tumors are an important area for therapeutic development. Overall survival (collection to last contact) for ERBB2, KRAS and MET CNA-High versus CNA-Low tumors, by Driver mutation status. [Table: see text]