bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of ctDNA tumor fraction (TF) on overall survival and concordance between tissue genomics and ctDNA in Lung-MAP.
Authors: Mack Philip C. , Redman Mary Weber , Kozono David E. , Callis Sam , Tukachinsky Hanna , Tolba Khaled A. , Neal Joel W. , Waqar Saiama Naheed , Dragnev Konstantin H. , Aggarwal Charu , Hirsch Fred R. , Patel Jyoti D. , Herbst Roy S. , Chiang Anne C. , Reckamp Karen L. , Kelly Karen , Borghaei Hossein , Gray Jhanelle Elaine , Gandara David R.
Published: June 2023

9035

Background: Discordance in genomic profiling between tumor tissue and ctDNA can occur due to inter-patient variability in shed tumor DNA, and intra-patient variability in sources of cell-free DNA (tumor heterogeneity, metastatic variants, CHIP). TF is an aneuploidy-based estimation of tumor-specific DNA in circulation. We evaluated the impact of TF levels on overall survival (OS), mutation concordance and tumor mutation burden in tissue (tTMB) and ctDNA (bTMB) in the LUNGMAP screening study. Methods: Eligible advanced NSCLC pts had blood drawn ≤30 days of fresh tissue biopsy with no intervening therapies. Genomic profiling was done by FoundationOne CDx and FoundationOne Liquid CDx. ctDNA TF was quantified via aneuploidy using deviations in genome-wide SNP coverage or somatic allele frequencies if under aneuploidy LoD. High TF was defined as ≥10%. Concordance among driver genes, cancer genes of interest (CGoI: T P53, PIK3CA, STK11, KEAP1, RB1, PTEN, ATM, BRCA1/2), and variant subtype were assessed by the percentage positive agreement (PPA) and positive predictive value (PPV) with 95% confidence intervals (CI). OS by TF used a Cox model and log-rank test. PPA and TF among CGoIs was compared with a Wilcoxon test. Correlation between tTMB and bTMB used Lin’s coefficient (LC). Results: 167 pts met inclusion criteria; 161 had TF data with 51 (32%) ≥10% (high TF). High TF was associated with worse OS (HR: 2.06 [1.43-2.95], p<0.001). The PPA and PPV ranged from 50%-100% and 60%-100%, respectively for driver genes. The PPA was numerically larger for high versus low TF for most drivers (p=0.18) and significantly larger for all mutations and SNVs combined (Table). For CGoI, the distribution of PPA differed between high and low TF (p=0.03). The median PPA for CGoI (25th%ile,75th%ile) was 56% (50,87) for low TF and 100% (100,100) for high TF. PPV for CGoI did not differ by TF (p=0.20). High TF was associated with higher levels of TMB and bTMB (p<0.01 for both). TMB LC (CI) for low and high TF were 0.46 (0.27,0.61) and 0.69 (0.53,0.81). Conclusions: High TF was associated with worse OS, better PPA among CGoI, and better LC for t/bTMB. TF may improve the clinical utility of mutations detected by liquid biopsies and should be reported and considered in interpreting these results. [Table: see text]
Uncommon EGFR mutations conducted with osimertinib in patients with NSCLC (UNICORN): A phase 2 study.
Authors: Okuma Yusuke , Kubota Kaoru , Shimokawa Mototsugu , Hashimoto Kana , Kawashima Yosuke , Sakamoto Tomohiro , Wakui Hiroshi , Murakami Shuji , Okishio Kyoichi , Hayashihara Kenji , Ohe Yuichiro
Published: June 2023

9045

Background: Non-small cell lung cancer (NSCLC) harboring uncommon EGFR mutation (uC- EGFRm), excluding exon 20 insertion, is a heterogenous rare fraction consisting of 10% of all EGFR mutations. Key drugs for metastatic NSCLC (mNSCLC) uC- EGFRm are limited, with only afatinib being FDA approved. Data on the efficacy of osimertinib for previously untreated metastatic patients (pts) harboring uC- EGFRm NSCLC is limited. Methods: UNICORN study for previously untreated mNSCLC pts harboring uC- EGFRm, excluding exon 20 insertion mutation, evaluating osimertinib with a dose of 80 mg QD orally is a multicenter, open-label, single-arm phase 2 study. The primary endpoint was the overall response rate (ORR) evaluated by central review according to the Response Evaluation Criteria in Solid Tumors (version 1.1), and key secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety. Results: Between March 2020 to May 2022, a total of 42 pts were registered. Among the eligible 40 pts, 45.0% were female; the median age was 72 years (range 39-88); 42.5% were never smokers or light smokers; 92.5% were adenocarcinomas, solitary uC- EGFRm/compound mutation ratio was 57.5%/42.5%. The most common mutations were G719X (50.0%), followed by S768I (25.0%), L861Q (20.0%), and others, including compound mutation data. The ORR was 55.0 % (90% confidence interval [CI]; 40.9-68.5), the DCR was 90.0 % (95% CI; 76.3-97.2), the mPFS was 9.4 months (95% CI; 3.7-15.2) after a median follow-up of 27.0 months, the mOS was not reached (NR) (95% CI, 19.23- NR), and the mDoR 22.7 months (95% CI; 9.43-NR). In solitary and compound mutations with uC- EGFR m NSCLC, ORR was 52.2%/58.8%, mPFS was 5.4 months/11.4 months, mOS 23.0 months/NR, and mDoR was 22.7 months/NR, respectively. Safety was similar to previous reports and Grade 3/4 AEs were reported in 8 of 36 pts (27.5%) and 12.5% of pts developed pneumonitis. All of the AEs were manageable and there were no treatment-related deaths. Conclusions: Osimertinib in mNSCLC pts harboring uC- EGFRm other than exon 20 insertions showed clinical activity with manageable toxicities. These results suggest that osimertinib can be considered as a treatment option for this specific population. Clinical trial registration: jRCTs071200002. The study was funded by AstraZeneca. Clinical trial information: jRCTs071200002 .
Safety and efficacy of immune checkpoint inhibitors in patients with cancer and pre-existing autoimmune disease: A systematic review and meta-analysis in non-small cell lung cancer.
Authors: Aung Wint Yan , Lee Chung-Shien , Morales Jaclyn , Kohn Nina , Rahman Husneara , Seetharamu Nagashree
Published: June 2023

9053

Background: Cancer patients with pre-existing autoimmune diseases (AID) have been traditionally excluded from clinical trials of immune checkpoint inhibitors (ICI) due to concerns for immune activation leading to toxicity. As indications for ICI expand, there is a need for robust data on safety and efficacy of ICI in cancer patients with AID. Existing studies examined a heterogenous group of cancers and do not include a comparison to cancer patients without pre-existing AID. Therefore, data are lacking concerning how safety and efficacy of ICI in this group of patients may differ from the general population and whether the results are generalizable to non-small cell lung cancer (NSCLC). Methods: We searched for studies consisting of NSCLC, AID, ICI, treatment response, and adverse events using database-controlled vocabulary terms. We systematically searched Medline (PubMed), EMBASE, Scopus, CINAHL, and Web of Science. We selected studies that included NSCLC and excluded abstracts, case reports, review articles, and articles lacking outcomes or populations of interest. Three authors (WA, CL, NS) independently reviewed all abstracts to determine study eligibility and quality. Study quality was assessed using the Newcastle-Ottawa Scale. Study data were pooled using random-effects meta-analysis. Results: Data were extracted from 24 cohort studies, consisting of 10,924 cancer patients, of which 4353 were NSCLC patients. Studies examined a broad spectrum of AID consisting of 1157 patients, of which 291 were NSCLC patients. Pooled analysis revealed an AID flare incidence of 36% (95%CI 27%-46%) in all cancers and 23% (95%CI 9%-40%) in NSCLC. Tests of subgroup difference revealed no significant difference in AID flares by organ system in all cancers and NSCLC (p = 0.602 and p = 0.19, respectively). Pre-existing AID was associated with a higher risk of de novo iRAE in all cancer patients (RR 1.38, 95%CI 1.16-1.65) and in NSCLC patients (RR 1.51, 95%CI 1.12-2.03). There was no difference in de novo grade 3-4 iRAE and tumor response between cancer patients with and without AID. However, in NSCLC patients, pre-existing AID was associated with a 2-fold increased risk of de novo grade 3-4 iRAE (RR 1.95, 95%CI 1.01-3.75) but also better tumor response in achieving a complete or partial response (RR 1.56, 95%CI 1.19-2.04). Conclusions: Pre-existing AID confers an increased risk of toxicity during ICI therapy. NSCLC patients with AID are at a higher risk of de novo grade 3-4 iRAE but are also more likely to achieve treatment response than those without AID. Multidisciplinary collaboration is paramount when considering ICI therapy in this patient population with careful calculation of risk and benefit as well as close monitoring for toxicity.
Phase II trial of lazertinib in patients with epidermal growth factor receptor (EGFR) mutation-positive (M+), metastatic non-small cell lung cancer (NSCLC) with asymptomatic or mild symptomatic brain metastases after failure of EGFR tyrosine kinase inhibitor (TKI) (KCSG LU20-15).
Authors: Hong Min Hee , Choi Yoon Ji , Ahn Hee Kyung , Keam Bhumsuk , Kim Yu Jung , Kim Ju Won , Kim Hye Ryun , Kang Jin-Hyoung
Published: June 2023

9054

Background: Central nervous system (CNS) metastases occur not infrequently, ultimately devastating consequences in advanced EGFR M+ NSCLC. Lazertinib, a 3rd-generation (G) EGFR-TKI, has shown potent antitumor activity in EGFR-mutant NSCLC. We conducted a phase II single-arm study of lazertinib in EGFR M+ NSCLC patients (pts) having CNS metastases to evaluate its CNS activity. Methods: The patients exhibiting CNS progression upon 1st or 2nd-G EGFR-TKIs with least one measurable CNS lesion were enrolled. The primary endpoint was intracranial objective response rate (iORR) in evaluable for response set (ERS). Secondary endpoints included iORR without T790M mutation, overall ORR (oORR), disease control rate (DCR), intracranial progression-free survival (iPFS) in ERS. Overall survival (OS) and safety analyses were performed in pts who received at least one dose of lazertinib. Cerebrospinal fluid (CSF) penetration was measured as exploratory biomarker study. Results: Of 40 pts enrolled, 38 were evaluable for tumor response. Nineteen pts harbored exon 19 deletion and 21 pts for exon 21 L858R and 30% of pts had radiologic evidence of leptomeningeal carcinomatosis (LM) with 2 cytological confirmed cases. Forty-five percent of pts received afatinib as first line treatment, followed by 42.5% of gefitinib and 12.5% of erlotinib. Baseline plasma samples of all the 40 patients obtained for liquid-based next-generation sequencing (Guardant360) and T790M was found in 5 pts prior to lazertinib treatment. iORR was 57.9% (22/38). iORR with T790M-negative, oORR, and DCR were 54.5%, 39.5%, and 97.4%, respectively. With median follow-up of 13.6 months, median iPFS and OS were not reached. Treatment-related adverse events (TRAEs) emerged in 85.0% of pts with most common TRAEs being skin rash (50.0%) and paresthesia (42.5%). Grade 3 or 4 TRAEs were reported in 10.0%. The CSF penetration rates of lazertinib and its metabolite (YH26334) were 46.2% and 33.1%, respectively in paired CSF and plasma samples, suggesting high CNS penetration efficacy. Conclusions: Lazertinib has substantial CNS activity regardless of T790M status against the progression of intracranial metastases ± LM during the treatment of 1st or 2nd-G EGFR-TKIs in metastatic EGFR M+ NSCLC pts. These results suggest that using lazertinib instead of brain local treatment would be a potential strategy in EGFR M+ NSCLC, who progressed on CNS metastases after prior EGFR-TKI. Clinical trial information: NCT05326425 . [Table: see text]
Impact of first-line immunotherapy on survival and intracranial outcomes from a real-world cohort of patients with non-small cell lung cancer with brain metastases at diagnosis.
Authors: Nigen Benoît , Mathiot Laurent , Goronflot Thomas , Herbreteau Guillaume , Sagan Christine , Raimbourg Judith , Bennouna Jaafar , Thillays Francois , Pons-Tostivint Elvire
Published: June 2023

9058

Background: Although brain metastases (BM) at diagnosis are common in non-squamous NSCLC patients (ns-NSCLC), they have been mostly excluded from randomized trials. The aim of this retrospective study was to evaluate real-word outcomes of frontline immune checkpoint inhibitor (ICI) in these patients. Methods: We conducted a retrospective study to assess the intracranial and overall efficacy of first-line ICI-based therapy compared to chemotherapy (CT) in ns-NSCLC patients diagnosed with BM, showing no targetable alterations. Patients were divided according to systemic therapy: CT, ICI, or CT-ICI respectively. Primary endpoint was overall survival (OS), compared using Kaplan-Meier and Cox methodology. Secondary endpoint was intracranial progression free survival (icPFS). Results: Between 01-2018 and 05-2021, 118 newly diagnosed ns-NSCLC patients with BM were included (52 CT, 38 ICI and 28 CT-ICI). Median follow-up was 30.0 months [95% CI: 25.9-36.0]. Intracranial radiotherapy was delivered for 75.0%, 68.4% and 67.9% of patients for CT, ICI and CT-ICI groups (p = 0.805) respectively. OS rates at 24 months were respectively 25.3% (95% CI: 15.7-40.9), 44.6% (95% CI: 30.8-64.7) and 50.5% (95% CI: 34.3-74.4) in CT, ICI and CT-ICI groups (p = 0.048). Twelve-month icPFS was respectively 17.0% (95% CI: 9-32), 47% (95% CI: 33-66) and 45% (95% CI: 30-69) in CT, ICI and CT-ICI groups . After adjustment, ICI and CT-ICI were associated with a better OS compared to CT (HR = 0.46, 95%CI: 0.23-0.89, p = 0.021 and HR = 0.52, 95%CI: 0.27-1.01, p = 0.054 respectively). ICI and CT-ICI were associated with a significant reduction in the risk of intracranial progression by 54% (HR = 0.46, 95%CI: 0.25–0.84, p = 0.0123) and 59% (HR = 0.41, 95%CI: 0.23–0.77, p = 0.0050) compared to CT. Stereotactic radiosurgery was associated with an increased icPFS compared to systemic therapy alone (HR = 0.51, 95% CI: 0.29 – 0.92, p = 0.0247), whereas whole-brain was not (p = 0.096). Conclusions: Real-life ns-NSCLC patients with BM at diagnosis treated frontline with ICI presented OS and icPFS benefit compared to CT alone. A prospective assessment of the ideal type and sequence of systemic and local therapy should be conducted.
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]
Dacomitinib for patients with non-small cell lung cancer harboring uncommon epidermal growth factor receptor mutations: Do mutation patterns matter?
Authors: Li Hong-Shuai , Lei Siyu , Xu Haiyan , Xing Puyuan , Yan Xiang , Wang Yan
Published: June 2023

9106

Background: Previous evidence has revealed the potential efficacy of dacomitinib in patients with advanced non-small cell lung cancer (NSCLC) carrying uncommon epidermal growth factor receptor ( EGFR) mutations, but it remains unknown whether there are differences in its efficacy for different combination patterns of these uncommon mutations. Methods: The AFANDA cohort, an ambispective cohort including 121 NSCLC patients with uncommon EGFR mutations admitted from two tertiary hospitals in China, was employed for exploration. Meanwhile, a cohort of 63 patients with common mutations was included for comparison. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed between groups. Results: A total of 133 patients with advanced or recurrent NSCLC that received dacomitinib were eligible for analysis. Baseline characteristics were balanced between subgroups. A significant difference was observed between patients with common mutations (C group, n = 63), common mutation plus uncommon mutations (C+U group, n = 24), and uncommon mutations (U group, n = 46) regarding to PFS (mPFS: 7.07, 8.17, and 11.97 months; p = 0.026). Moreover, the highest ORR and DCR of the U group were observed among subgroups, although the differences were not statistically significant (ORR, 40.4%, 40.9%, and 61.4%; p = 0.085; DCR, 78.9%, 72.7%, 90.9%; p = 0.134). Furthermore, the multivariate analysis revealed that the mutation pattern was an independent prognostic indicator of PFS ( p = 0.049), with the C+U group having the highest risk of progression (HR [hazard ratio]: 1.438, 95% CI [confidence interval]: 0.818-2.528) while the U group having the lowest one (HR: 0.666, 95% CI: 0.409-1.084). For toxicity analysis, no significant difference was observed regarding grade 3-4 AEs among subgroups (12.7%, 8.3%, 13.0%; p = 0.827). The drug resistance analysis did not reveal a significant difference concerning the secondary T790M mutation rate (26.3%, 0%, 13.3%; p = 0.331). Conclusions: Dacomitinib demonstrated different therapeutic efficacy for patients with NSCLC harboring different combination patterns of uncommon EGFR mutation, which should be considered in clinical trials' design and clinical application. [Table: see text]
Association between real-world, upfront, next-generation sequencing and overall survival (OS) in advanced non–small-cell lung cancer (aNSCLC) in the United States.
Authors: Levy Benjamin Philip , Nguyen Danny , Shih Yu-Hsuan , Gorritz Magdaliz , Cai Beilei , Caro Nydia , Yasuda Marie , Gu Yifan , Chen Chi-Chang , Pretre Vincent , Saliba Teddy Rassem
Published: June 2023

9117

Background: Multiple biomarker testing strategies exist as the treatments of aNSCLC rapidly evolve. While upfront NGS is considered optimal, this practice has not been universally adopted. Surprisingly, the impact of NGS vs non-NGS approaches on OS is unclear, with the largest study to date demonstrating lack of benefit. We aim to identify the genomic testing strategy associated with the most optimal OS in aNSCLC using data from a large, contemporary electronic health record (EHR) database. Methods: This retrospective study used Flatiron EHR data. Patients diagnosed with aNSCLC between 11 Apr 2019 and 31 Dec 2021 who received systemic therapy were identified and followed from the date of diagnosis to 31 May 2022 or death. Testing methods reported within the patient’s chart were extracted. Methods assessed included NGS (defined as any test type with ‘NGS’ as test name) and non-NGS (defined as PCR, FISH, IHC, and other sequencing methods not containing ‘NGS’). Upfront testing was defined as tests received on or prior to the date of initiation of first-line (1L) therapy. Kaplan-Meier analyses were used to estimate and compare real-world overall survival (rwOS) by testing strategies. Among those with actionable genetic mutations, we also explored rwOS by timing of targeted therapy (TT) initiation. Results: Of a total 13,139 patients, mean age was 69, 49% female, 64% white, 33% Medicare insured, and 88% treated in community setting only. Median follow up time was 9 months. The percentage of patients with upfront NGS increased from 29% in 2019 to 66% in 2022. Median OS (mOS) was longest in patients with upfront NGS compared to those with upfront non-NGS genomic tests (p < 0.05), those with NGS after 1L (p < 0.05), and those with no NGS test ever (p < 0.05) (see table). 19% of patients with upfront NGS vs. 15% of those with upfront non-NGS received TT in 1L; 23% of patients with NGS vs. 19% of those with upfront non-NGS received TT at any line of therapy. In patients with actionable genetic mutations, mOS decreased with later initiation of TT; mOS was not reached (NR) (34.6 – NR) in patients who initiated TT in 1L, 34.7 (29.1 – NR) months in those with 2L TT, and 24.3 (20.3 – 30.1) months in those who initiated TT in 3L. Conclusions: This is the first and largest study to demonstrate that upfront NGS testing leads to better OS when compared to upfront non-NGS genomic testing, later NGS, or no-NGS in aNSCLC. In line with these results, we also found an OS benefit associated with earlier TT initiation. These results highlight the significant impact of upfront NGS testing and underscore for the need for both education and wider accessibility of NGS testing. [Table: see text]
FDA analysis of toxicity profiles of oral TKIs recently approved for non-small cell lung cancer based on receipt of prior immune checkpoint inhibitor therapy.
Authors: Liu Yufan , Duke Elizabeth , Drezner Nicole Lauren , Singh Harpreet , Kluetz Paul , Pazdur Richard , Larkins Erin A.
Published: June 2023

9119

Background: Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 are standard front-line therapy for advanced non-small cell lung cancer (NSCLC). Molecularly targeted tyrosine kinase inhibitors (TKIs) are standard of care for subsets of oncogene-driven NSCLC. Published literature suggests the possibility of increased toxicity in patients who receive ICIs followed by EGFR or ALK TKI treatment. However, the toxicity profile in patients who receive ICIs followed by TKIs with other genomic targets has not been well described. Methods: Marketing applications for TKIs in patients with NSCLC submitted to the Office of Oncologic Diseases between Jan 2019 to Dec 2022 were reviewed. Datasets were analyzed for demographics, treatment-emergent adverse events (TEAE), and prior anti-cancer therapies for TKI-treated patients in the primary efficacy population. Drug classes for which < 5% of patients received prior ICI were excluded. Grade 3-4 TEAE, serious adverse events (SAE), discontinuation TEAE and TEAE of interest (hepatotoxicity, rash, and interstitial lung disease [ILD]) were summarized. Results: 9 applications were identified and 2 were excluded. The remaining applications involved TKIs targeting EGFR exon 20 insertion, KRAS G12C, MET exon 14 skipping, and RET fusion alterations. Analyses included 867 patients; 61% received prior ICI therapy. Patient characteristics and results of analyses are presented in the table. In our pooled analysis, the incidence of Grade 3-4 AEs, SAEs, and hepatotoxicity were slightly higher in the prior ICI group, while the incidence of discontinuation TEAE, ILD, and rash were similar between groups. Analysis for hepatotoxicity was limited to reported AEs (did not include analysis of laboratory data). Review of toxicity data across individual drug classes did not show major differences compared to the overall results. Conclusions: Our analysis of safety data for newer TKIs with varied genomic targets does not appear to show excessive toxicity in patients with NSCLC who received prior ICI compared to those who did not. In future clinical trials evaluating TKIs in this population, inclusion of patients who have received prior ICI therapy should be considered when appropriate. [Table: see text]
Phase II randomized trial of first-line pembrolizumab and vorinostat in patients with metastatic NSCLC (mNSCLC): Final results.
Authors: Saltos Andreas Nicholas , Tanvetyanon Tawee , Creelan Ben C. , Shafique Michael Rahman , Antonia Scott Joseph , Haura Eric B. , Zheng Hong , Yu Xiaoqing , Saller James Joseph , Viracacha Sebastian , Thapa Ram , Boyle Theresa A. , Chen Dung-Tsa , Beg Amer A , Gray Jhanelle Elaine
Published: June 2023

9125

Background: Histone deacetylase inhibitors enhance tumor immunogenicity through various mechanisms including induced expression of MHC and T cell chemokines. A previous phase I trial demonstrated the combination of pembrolizumab (P) with vorinostat (V) in advanced/metastatic (m)NSCLC was well tolerated with signals of activity in ICI-pretreated pts. To further investigate the combination, we conducted a first-line, phase II trial. Methods: Pts with treatment-naïve mNSCLC and tumor PD-L1 expression ≥ 1% were eligible. Pts were randomized, open-label, 1:1 to receive P 200 mg IV q3 wk as monotherapy [Arm A] vs P 200 mg IV q3 wk plus V 400 mg PO daily [Arm B]. The primary endpoint was overall response rate (ORR). Secondary endpoints included DOR, PFS and OS. Tumor biopsies were collected both pre- and on-treatment (day 15-21) for exploratory correlative analysis including gene expression and changes in the tumor microenvironment. Results: Between 7/2017 – 2/2022, 86 pts were enrolled, with 83 pts evaluable for response (40 in Arm A and 43 in Arm B). Median age was 69 (range 44 - 87), 47% female, and ECOG PS 0/1 in 9%/91%. PD-L1 TPS was ≥50% in 20/40 (50%) of pts in Arm A, and in 23/46 (50%) of pts in Arm B. The most common TRAEs in Arm A included diarrhea (15%) and fatigue (10%). 3 pts in Arm A experienced grade ≥ 3 irAEs (including 1 each of grade 3 hepatitis, pneumonitis, and rash). The most common TRAEs in Arm B included fatigue (41%), nausea (44%), diarrhea (35%) and increased creatinine (33%). 3 pts in Arm B experienced grade ≥ 3 irAE (2 grade 3 pneumonitis and 1 grade 4 myopericarditis). In Arm B, 22/45 (49%) of pts had a dose-reduction in vorinostat, most commonly due to grade 2-3 fatigue or nausea. Efficacy results by intention-to-treat are summarized in the Table below. For evaluable patients only, ORR was 44% in Arm B (19/43) and 28% in Arm A (11/40) (p=0.18). RNA-sequencing of a subset of patients showed a significant increase in interferon-γ pathway activity in both Arms. However, between the two Arms, interferon-γ pathway activity was enhanced to greater extent in Arm B, which may have contributed the higher overall response rate. Conclusions: To our knowledge, this is the first randomized trial investigating the combination of HDAC inhibition and anti-PD1 therapy in NSCLC. Although the combination arm had a numerically higher ORR compared to P monotherapy, the result did not meet the primary endpoint for significance. While there were no new safety signals with the combination therapy, reduction or interruption in V dose occurred frequently, which may have contributed to lack of survival differences between arms. Clinical trial information: NCT02638090 . [Table: see text]