Advanced Non-small Cell Lung Cancer Pts Research Articles

Genomic instability in advanced non-small cell lung cancer (NSCLC) treated with maintenance durvalumab in the UNICANCER SAFIR02-Lung/ IFCT1301 trial.

2632 Background: Genomic instability is a hallmark of cancer that has been associated to immune evasion, cancer progression and multidrug resistance. In SAFIR02-Lung, advanced NSCLC pts were enrolled to receive a platinum-based chemotherapy. After 4 cycles, pts with no targetable alterations were oriented to the immunotherapy sub-study, and if stable or in response, were randomized between maintenance durvalumab or Standard of Care (SoC) (PMID 35802649). Durvalumab prolonged survival only in the PD-L1 ≥ 1% subgroup. In this study we investigated a genomic instability score based on somatic copy number alterations as determined by Comparative Genomic Hybridization (CGH) array as a biomarker for maintenance immunotherapy. Methods: SAFIR02-Lung (NCT02117167) is a multicentric, randomized phase 2 clinical trial. Tissue samples were obtained before induction chemotherapy. Extracted DNA from fresh frozen tumor was analyzed using high-resolution Affymetrix Cytoscan arrays, DNA from FFPE samples was analyzed using the Affymetrix Oncoscan CNV platform. The absolute copy-number (ACN) profile was generated by ASCAT v3.1 through EaCoN v0.3.6 ( https://github.com/gustaveroussy/EaCoN , PMID 36669143 ) on R v4.1.1 and then the genomic instability score was estimated as the sum of the segment length multiplied by the absolute difference between segment copy number and the ASCAT estimated sample ploidy. This sum is reported to the reference genome length. Progression Free Survival (PFS) was the primary endpoint, defined as the time from randomization until the date of objective radiological disease progression, clinical progression or death. The secondary endpoint was Overall Survival (OS). Results: CGH array data were available for 79 patients out of 183, 56 randomized to durvalumab and 23 to SoC. 47 were men, 72 had non-squamous histology and 12 had brain and 10 had liver metastasis. We divided patients in tertiles according to instability (INS) score. No correlation was seen between INS score and PD-L1 positivity (p = 0.5), or liver and brain metastasis. Pts with high INS had lower median PFS of 2.5 months (m) (95% CI 1.4 – 5.2) vs 4.3m (95% CI 2.6 – 13.7) for those with intermediate INS and 6.1m for those with low INS (95% CI 1.9 – 21.2), p 0.012. Similarly, low INS patients had longer OS of 29.6 m (95% CI 15.4 – NR) vs 17.9m for intermediate INS (95% CI 10 – NA) and 12.1m for high INS (95% CI 10.2 – 19.5), p = 0.039. No difference was seen in the control group (p=0.25 for PFS and p=0.4 for OS). A multivariable model showed that high INS was independently associated worse PFS (HR 2.60, 95% CI 1.36 - 4.98, p 0.004) and OS (HR 2.90, 95% CI 1.33 - 6.35, p 0.008). Conclusions: Genomic instability score based on CGH array-based copy number alterations profile is associated with worse PFS and OS in patients under response to chemotherapy who received durvalumab maintenance. Clinical trial information: NCT02117167 .

Abstract CT247: Updated efficacy and safety of anti-TROP2 ADC SKB264 (MK-2870) for previously treated advanced NSCLC in Phase 2 study

Abstract Background: TROP2 (trophoblast cell surface antigen 2) is commonly over-expressed in non-small cell lung cancer (NSCLC) and associated with poor prognosis. SKB264 (MK-2870) is a TROP2 ADC developed with a novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor. The linker is affected by both extracellular pH-sensitive cleavage and intracellular enzymatic cleavage within tumor cells, which leads to efficiently release payload inside tumor cells as well as within tumor microenvironment to exert its anti-tumor effects. Here, we present the updated data from a Phase 2 expansion cohort for patients (pts) with advanced NSCLC. Methods: Pts with previously treated advanced NSCLC were enrolled to receive SKB264 at 5 mg/kg Q2W until disease progression or unacceptable toxicity (KL264-01, NCT04152499). Tumor assessment was performed every 8 weeks per RECIST v1.1 assessed by investigator. Results: As of Nov 22, 2023, 43 NSCLC pts had been enrolled. Median follow-up was 17.2 months (mo). 21 pts with EGFR wild type had received median prior 3 regimens of therapy including anti-PD-1/L1 inhibitors. 22 pts with EGFR mutant had progressed on or after TKI therapy, 50% of whom also failed at least one line of chemotherapy. Updated efficacy results are shown in the Table. Overall, 30 pts (69.8%) experienced Grade ≥3 treatment-related adverse events (TRAEs). The most common Grade ≥3 TRAEs were neutrophil count decreased (34.9%), anemia (30.2%), WBC count decreased (25.6%), stomatitis (9.3%), and rash (7.0%). No TRAEs leading to treatment discontinuation or deaths occurred. No drug-related ILD/pneumonitis was reported. Conclusions: The updated data continues to demonstrate that SKB264 monotherapy delivers promising clinical efficacy with manageable toxicity in pretreated advanced NSCLC pts. A Phase 3 global study of SKB264 in pts with 3L+ EGFR mutant NSCLC (NCT06074588) and a Phase 3 study of SKB264 in China in pts with 2L EGFR mutant NSCLC (NCT05870319) are ongoing. TABLE 1: NAND Table Clinical outcomes by EGFR mutation status Overall (N=43) EGFR mutant (N=22) EGFR wild type Total (N=21) Non-squamous (N=9) Squamous (N=12) ORR*, % 43.6% 60.0% 26.3% 22.2% 30.0% Median DoR, mo (95%CI) 9.3 (3.7, 10.3) 8.7 (3.7, 10.3) 9.6 (3.5, NE) / / Median PFS, mo (95% CI) 7.2 (5.4, 11.3) 11.5 (5.7, 12.9) 5.3 (3.5, 6.2) 5.8 (1.5, 12.1) 5.1 (1.9, 9.3) Median OS, mo (95% CI) 22.6 (13.1, NE) 22.7 (19.7, NE) 14.1 (10.7, NE) 16.2 (5.8, NE) 12.8 (3.5, NE) 12-mo OS rate, % (95% CI) 69.0% (52.7, 80.7) 81.0% (56.9, 92.4) 57.1% (33.8, 74.9) 66.7% (28.2, 87.8) 50.0% (20.8, 73.6) 18-mo OS rate, % (95% CI) 56.5% (40.1, 70.0) 76.2% (51.9, 89.3) 35.9% (16.0, 56.4) 44.4% (13.6, 71.9) 30.0% (7.7, 56.9) *Including confirmed or unconfirmed response. Based on response evaluable pts (≥1 on-study scans) with 4 pts (2 EGFR mutant pts with non-squamous histology and 2 EGFR wild type pts with squamous histology) excluded. Citation Format: Wenfeng Fang, Ying Cheng, Zhendong Chen, Wei Wang, Yongsheng Li, Yongmei Yin, Xingya Li, Huiting Xu, Guohua Yu, Yanjun Mi, Zev A. Wainberg, Jordi Rodon, Xiang Wang, Xian Wang, Xiaoqing Zhang, Xiaoping Jin, Lian Lu, Junyou Ge, Jin Li, Li Zhang. Updated efficacy and safety of anti-TROP2 ADC SKB264 (MK-2870) for previously treated advanced NSCLC in Phase 2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT247.

Abstract 5037: Development of multiplexed Absolute Q digital PCR assays to rapidly quantify EGFR and KRAS genotype in advanced non-small cell lung cancer (NSCLC) patients’ plasma

Abstract Introduction: There are needs to identify and serially monitor driver and resistance mutations (muts) in therapy-treated cancer patients (pts). Quantitative liquid biopsy in cell-free (cf)DNA has been widely adopted. We have developed and clinically validated droplet digital PCR (ddPCR) assays to detect common driver/resistance muts such as EGFR del19, L858R, T790M and KRAS G12X in the cfDNA of advanced NSCLC pts. We have established ddPCR assays for 30+ driver/resistance muts in multiple genes (BRAF, MET, ESR1, etc.) relevant to melanoma, breast, and colorectal cancer. Our assays use tumor/cell line DNA as positive controls and serve as benchmarks to develop newer assays such as plasma NGS. In this study, we converted existing/validated EGFR and KRAS G12X ddPCR assays to the QuantStudio Absolute Q digital PCR (dPCR) system. The selected mutations maximize actionable clinical information and are designed to study oncogenic and resistance mutations in NSCLC efficiently. dPCR’s accuracy and efficiency enables target multiplexing, providing comprehensive information from limited materials and contributing to liquid biopsy research progress. Methods: Plasma from pts with tumors harboring EGFR and KRAS muts was collected at progression with advanced disease following consent to protocol DFCI #14-147. We designed a multiplex dPCR assay that identifies the most common and therapy-relevant KRAS muts in NSCLC, G12C/D/V, and detects other G12X using a drop-off probe. We also designed 2 EGFR kits, one identifying driver muts, the other resistance muts. Results: To validate assay performance, we used gDNA derived from cell lines with EGFR or KRAS muts. We serially diluted mut gDNA samples in background wt gDNA (16 ~ 1000 mut copies in 1000 wt copies) and performed KRAS and EGFR dPCR assays. We detected 16 mut copies with sensitivities similar to those of ddPCR assays. We then studied 48 cfDNA samples from plasma of NSCLC pts with tumor confirmed KRAS G12X or EGFR L858R, del19, T790M muts. No samples had both EGFR and KRAS muts detected, suggesting our assays are specific. We detected muts in samples with an allele frequency median of 0.9% for KRAS mut, 11.9% for EGFR driver mut, 2.9% for EGFR T790M. The concordance rate is 91.3% between dPCR and ddPCR results. Our findings suggest these assays are as sensitive and specific as our validated ddPCR assays. Multiplexed Absolute Q dPCR saves cfDNA and cuts turnaround time (TAT) to 90 min for KRAS assay and 3hr for EGFR assays. Conclusions: We developed rapid, sensitive and specific quantitative dPCR assays for KRAS and EGFR muts on the QuantStudio Absolute Q platform to quantify plasma genotyping in NSCLC. We will clinically pilot our validated rapid genotyping approach and quantify TAT advantage of multiplexed genotyping in NSCLC pts undergoing standard-of-care tumor genotyping. Citation Format: Benjamin Hanna, Shidong Xu, Cloud P. Paweletz, Yanan Kuang. Development of multiplexed Absolute Q digital PCR assays to rapidly quantify EGFR and KRAS genotype in advanced non-small cell lung cancer (NSCLC) patients’ plasma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5037.

A phase III, multicenter, double-blinded, randomized, active-controlled study on the efficacy and safety of QL1706 with chemotherapy (CT) as first-line therapy for PD-L1–negative advanced or metastatic non–small-cell lung cancer (NSCLC).

TPS9139 Background: PD-(L)1 immunotherapy plus platinum-doublet chemotherapy has been the standard 1L treatment for EGFR/ALK wild-type advanced NSCLC pts. However, pts with PD-L1 negative achieve minimal benefit from the PD-(L)1 immunotherapy plus CT. PD-(L)1 plus CTLA-4 blockade with CT in 1L treatment of PD-L1 negative NSCLC derived an improved median overall survival (OS) versus CT alone in CheckMate-9LA study ( Luis Paz-Ares et al., Lancet Oncol 2021) and POSEIDON study ( M L. Johnson et al., JCO 2022). QL1706 is a novel bifunctional antibody, containing a mixture of anti-PD-1 IgG4 and anti-CTLA-4 IgG1 antibodies produced in a fixed ratio (2:1) from the same single cell and manufactured together as one product (MabPair). QL1706 monotherapy or plus CT showed impressive safety and efficacy in advanced NSCLC both in phase I and phase II studies (data have been submitted for publication). Of note, QL1706+CT exhibited promising antitumor activity in advanced PD-L1 negative NSCLC. The phase III study aims to compare the efficacy of QL1706+CT versus anti-PD-1 (tislelizumab) + CT (approved in China for 1L treatment of mNSCLC) as 1L treatment in advanced PD-L1 negative NSCLC. Methods: The phase III, multicenter, double-blinded, randomized, active-controlled study is enrolling pts aged 18-75 years with ECOG PS of 0-1, previously untreated, PD-L1 negative (TPS < 1%), EGFR/ALK wild-type, and pathologically identified stage IIIB-IV NSCLC. Eligible pts will be randomized (1:1) to receive 4-cycle treatment of QL1706 (5 mg/kg, Q3W) plus CT or tislelizumab (200 mg, Q3W) plus CT followed with maintenance treatment of QL1706 or tislelizumab monotherapy (squamous), or in combination with pemetrexed (non-squamous), until disease progression, intolerable toxicity, or for up to 2 years of immunotherapy. Stratification factors include histology (squamous vs non-squamous), brain metastasis (yes vs no), and sex (male vs female). Co-primary endpoints are progression-free survival (PFS) and OS. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), duration of response (DOR) assessed by investigator per RECIST v1.1, 6 mo- and 12 mo-PFS, 6 mo- and 12 mo-OS, and safety. Exploratory endpoints include PK characteristics, immunogenicity, PFS2 (defined as time from randomization to progression after first subsequent therapy or any-cause death), and efficacy (iPFS, iORR, iDCR, iDOR) by investigator per iRECIST, biomarker analysis of tumor mutation burden. The study planned to enroll 650 pts to obtain approximately 493 PFS events (HR = 0.69; Power = 94%) and 445 OS events (HR = 0.75; Power = 83%) across the QL1706+CT and tislelizumab+CT arms for the final analyses of PFS and OS, respectively. The alpha was split between PFS (α = 0.005) and OS (α = 0.02). Enrollment began from Feb 2023. Clinical trial information: NCT05690945 .

Explore ALK: Alectinib activity in patients with ALK+ metastatic non-small cell lung cancer—A national real world analysis (GFPC 03-2019).

9092 Background: Alectinib is a standard of care option in advanced ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) patients (pts), with efficacy established by phase 3 trials, in first-line and beyond. There are few efficacy data in unselected populations. Methods: The objective of this study was to evaluate the efficacy of alectinib in real-world setting. All ALK+ advanced NSCLC pts initiating alectinib, between December 13, 2017 (date of access in France) and June 27, 2020, whatever the line, were included in explore ALK study. Patient characteristics, alectinib duration of treatment (DOT), progression-free survival assessed locally (rwPFS), overall survival (OS) according to the prescription line of alectinib, the presence of brain metastases at alectinib initiation, response rate and tolerance were collected from the medical files. Results: The analysis included 223 pts: 46.2% were men, 84.7% had no smoking history or were former smokers, median age was 59 (22-101) years and 95% were adenocarcinomas. Alectinib was initiated as first-line treatment in 119 pts, with a PS of 0/1/>1 in 42%/31%/27% of cases, a median number of metastatic sites of 2 (cerebral, hepatic, bone in 33%, 24% and 32% of cases). In first-line setting, after a median follow-up of 33.7 months (95%CI, 32.2-37.5), the median of rwPFS and DOT were 28.1 (95%CI, 20.7-40.4) and 26.9 (95%CI, 20.2-31.3) months, respectively. The median OS was not reach (NR), the 3-year OS rate was 72.1%. The rwPFS was not significantly different depending on whether or not the patient has brain metastases, 28.1 (95% CI, 14.5-NR) and 30.5 (85% CI, 18.9-40.4) months, respectively. The best response was complete (CR), partial (PR) and stable (SD) in 21%, 58% and 17%. The cerebral response, evaluable in 30/39 of the pts, was CR, PR and SD in 26%, 46% and 23% respectively; 33% of pts had a grade 3 adverse event, resulting in a temporary interruption of treatment in 7.6% of cases and a permanent discontinuation in 5.9% of cases. At the time of progression, 48.1% of pts had a new biopsy (66% of tissue biopsy). Efficacy data for alectinib prescribed as second line and above are summarized in the table. Conclusions: In this large real-world, cohort of unselected advanced ALK+ NSCLC pts, alectinib initiated in 1st-line or beyond provides similar efficacy and safety results as obtained in phase III clinical trials. [Table: see text]

Clinical characteristics and treatment outcome of patients with advanced non-small-cell lung cancer (NSCLC) and FGFR fusions.

e21139 Background: Activating FGFR fusions are targetable genetic alterations in several solid tumours and hematologic malignancies, but little is known about their frequency in advanced NSCLC patients (pts). Furthermore, clinical characteristics and treatment outcome in NSCLC have not been sufficiently identified yet. Methods: Within Network Genomic Medicine (NGM), we screened advanced NSCLC pts without targetable mutations for genetic fusions using RNA-NGS (ArcherDx FusionPlex) and analysed fusion frequencies, patient characteristics and clinical courses. Results: From 01/2019 to 09/2022, we screened a total of 3309 NSCLC pts. We found 37 pts (1.1%) with FGFR activating fusions. Of these patients, 26 cases had squamous cell carcinoma (70.3%), 10 cases adenocarcinoma (27%), one patient had sarcomatoid differentiation (2.7%). The most common FGFR fusion was FGFR3-TACC3 with 21 cases (56.8%). All patients had UICC stage IIIB or IV at time of diagnosis: 13 were females (35.1%), 24 were males (64.9%); median age at first diagnosis was 69 years (range 36-91), 27 pts were former smokers (72.9%), 8 pts were current smokers (21.6%) and only one patient was a never smoker (2.7%). Co-occurring mutations were identified in 30 pts (81.1%): TP53 co-mutations were the most frequent co-mutation with 27 cases (72.9%), two cases had KEAP1 (5.4%), one case harboured either PTEN (2.7%), PIK3CA (2.7%) or MAP2K1 (2.7%). One patient harboured FGFR2 S587C co-mutation (2.7%). From 37 identified patients, 34 were available for follow-up. The median overall survival (mOS) was 24.87 months (95% confidence interval [CI]: 11.57–38.17). We counted 26 pts who received immunotherapy (either as monotherapy or chemoimmunotherapy) with a mOS of 26.44 months (95% CI: 20.23–32.66) comparing to the median OS of 9.5 months for patients (n = 8) with no immunotherapy (95% CI: 0.0–22.58) (p = 0.037). For three patients there was no information regarding therapy regimen obtainable. Six pts (16.21%) received targeted therapy (Erdafitinib/Rogaratinib) with no improved mOS compared to standard therapy (p = 0.026). Patients with TP53 mutation had longer mOS than pts with TP53 wild type (WT) (mOS 26.45 months [95% CI: 20.06–32.83] vs 9.24 months [95% CI: 1.43–17.06] [p = 0.031]). Conclusions: Activating FGFR fusions in NSCLC are rare events. The majority of patients are elder males with smoking history and predominantly squamous histology. The most frequent co-mutation is TP53 with prolonged OS comparing to TP53 WT patients. In contrast to other NSCLC with targebatle driver mutations, patients with FGFR fusion seem to benefit from immunotherapy, if added to their treatment. Targeted therapy is beneficial, but sufficient long-term data are currently missing.

Differential efficacy of tyrosine kinase inhibitors (TKIs) according to the types of EGFR mutations and agents in non-small cell lung cancer (NSCLC): A real-world study.

e21040 Background: Both 1st and 2nd-generation (gen) EGFR-TKIs are recommended in advanced NSCLC with common EGFR mutations. However, there are few data about the difference in the efficacy of EGFR-TKIs according to types of EGFR mutations and agents. Methods: This retrospective real-world study evaluated the outcome and clinicopathologic characteristics including the type of EGFR mutations in 237 advanced NSCLC patients (pts) treated with 1st or 2nd-gen (afatinib) EGFR TKIs as first-line therapy. Results: The median progression-free survival (PFS) and overall-survival (OS) of all pts were 11 months (M) and 25M, respectively. In univariate analysis, pts with exon 19 deletion (del) (n = 130) had significantly longer median OS compared to those with other mutations (L858R: 84, others: 23) (30 vs. 22 M, p = 0.047), without difference in PFS (p = 0.138). Pts treated with afatinib (n = 60) showed significant longer median OS compared to those treated with 1st gen TKIs (gefitinib: 159, erlotinib: 18) (30 vs. 23 M, p = 0.037). In pts with exon 19 del, there was no significant difference in median PFS (p = 0.868) and OS (p = 0.361) between pts treated with afatinib and those with 1st gen TKIs, while significantly better PFS (p = 0.042) and trend in OS (p = 0.069) were observed in pts receiving afatinib in other mutations. Exon 19 del was independently associated with favorable OS (p = 0.028), while age > 70 years (p = 0.017), ECOG performance status ≥2 (p = 0.001), primary metastatic disease (p = 0.007), and synchronous brain metastasis (p = 0.0026) were independent prognostic factors of poor OS. Conclusions: The EGFR exon 19 del was associated with favorable OS in advanced NSCLC pts receiving first-line EGFR TKIs. Moreover, in pts with exon 19 del, first generation TKIs seem to be a reasonable option if osimertinib is unavailable.

Association of ctDNA tumor fraction with survival in advanced non-small cell lung cancer (NSCLC) treated with maintenance durvalumab in the UNICANCER SAFIR02-Lung/IFCT1301 trial.

2516 Background: ctDNA shed is a promising biomarker for cancer immunotherapy, with patients (pts) having higher concentration of plasma ctDNA being reported to have poorer outcome. Its role in the maintenance setting with immune checkpoint inhibitors remains unexplored. In SAFIR02-Lung, advanced NSCLC pts were enrolled to receive a platinum-based chemotherapy. After 4 cycles, if stable or in response, pts with no targetable alterations were oriented to the immunotherapy sub-study and randomized between maintenance durvalumab or Standard of Care (SoC) (PMID 35802649). Durvalumab prolonged survival only in the PD-L1 ≥ 1% subgroup. Here we explored Tumor Fraction (TF) as determined by Low-Pass Whole Genome Sequencing as a biomarker for immunotherapy irrespective of PD-L1. Methods: SAFIR02-Lung (NCT02117167) is a multicentric, randomized phase 2 clinical trial. Plasma samples were obtained at randomization, just before maintenance treatment initiation. DNA was extracted using the Maxwell RSC ccfDNA Plasma Kit (Promega, AS1840). Sequencing libraries were prepared using the Low Input SureSelectXT protocol (Agilent, G9916A). Pooled libraries were sequenced on a NovaSeq 6000 platform (Illumina) as 2 × 150 bp paired-end reads (NovaSeq 6000 SP Reagent Kit v1.5). Genomic copy number aberrations and TF were investigated using the ichorCNA (V0.2.0) tool. TF ≥ 2% was considered positive. For the survival analyses, a landmark approach was performed, by considering the randomization date as the landmark time. Progression Free Survival (PFS) was the primary endpoint, defined as the time from randomization until the date of objective radiological disease progression, clinical progression or death. The secondary endpoint was Overall Survival (OS). Results: 50 out of 121 plasma samples from pts randomized to durvalumab were analyzed for the feasibility part. 34 pts (68%) were < 65 years, 33 (66%) were male. PD-L1 expression was available for 18 pts and 39% of them had PD-L1 ≥ 1%. Median TF was 1.1%, 8 pts (16%) had a TF ≥ 2%, ranging from 2.2% to 23.3%. TF at randomization was marginally correlated with the presence of liver metastases (p 0.063) and with the sum of target lesions (p 0.081). No significant correlation was observed with PD-L1 positivity. Pts with TF ≥ 2% had lower median PFS 1.7months (m) (95% CI 1.2 – 4.2) vs 5.8m (95% CI 2.9 – 7.5) for those with TF < 2%, p 0.0003. Similarly, median OS was lower for pts with TF > 2% 10.4m (95% CI 4.2 – 18.7) vs 25.9m (95% CI 18.2 – NR) for those with TF < 2%, p 0.0002. Data will be presented on the whole cohort, including control group receiving SoC, to discriminate between a prognostic or a predictive value of TF. Conclusions: TF was positive in 16% of pts randomized to durvalumab in the SAFIR02-Lung trial. This population seems to have a limited benefit from maintenance durvalumab after induction chemotherapy. Clinical trial information: NCT02117167 .

Association between duration of immunotherapy and overall survival in advanced non–small-cell lung cancer.

9101 Background: For patients (pts) with advanced non-small cell lung cancer (NSCLC) treated with front line immunotherapy-based treatment, the optimal duration of immune checkpoint inhibitor (ICI) treatment is unknown. We aimed to assess practice patterns surrounding ICI treatment discontinuation at two years, and to evaluate association of duration of therapy with overall survival by comparing pts who received fixed duration ICI therapy for 2 years vs those who continued therapy beyond two years. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database, and included adult pts diagnosed with advanced NSCLC from 2016-2020, who received frontline immunotherapy-based treatment. Pts who were still on treatment without progression at 2 years were classified as “fixed duration” (treatment discontinuation at 2 years, between 700-760 days) vs “indefinite duration” (continued treatment beyond two years, > 760 days). Overall survival from 760 days was analyzed using Kaplan-Meier methodology. Multivariable Cox regression adjusted for patient and cancer-specific factors was used to compare survival between fixed and indefinite-duration groups. Results: Our analytic cohort consisted of 113 pts in the fixed duration group and 593 in the indefinite duration group; median age was 69, 49% were female, and 71% were White. Pts in the fixed duration group were more likely to have a history of smoking and be treated at an academic center. There was no significant difference in overall survival between pts in the fixed duration and indefinite duration groups, either on univariable (HR 1.26, 95% CI 0.77-2.08) or multivariable Cox regression (HR 1.33, 95% CI 0.78-2.25). Conclusions: In a real world cohort of advanced NSCLC pts treated with front line ICI, only about 1 in 5 stopped treatment at two years rather than continuing treatment beyond two years. The lack of significant overall survival advantage for the indefinite duration cohort on adjusted analysis provides reassurance to pts and providers who wish to stop therapy at 2 years.

Clinical and molecular features of long-term response to anti-PD-(L)1 therapy in patients with advanced non-small cell lung cancer.

9107 Background: PD-(L)1 blockade can generate long-term responses in subsets of patients (pts) with advanced non-small cell lung cancer (NSCLC), but the clinical and molecular features of long-term responders (LTR) are not well established. Whereas features predictive of initial response have been rigorously explored, long-term follow up in large cohorts is required to identify features distinguishing LTR from short-term responders (STR). Methods: We analyzed pts with advanced NSCLC treated with anti-PD-(L)1 therapy at three institutions (MSK, DFCI, MDACC) between 2011 and 2022; responses were assessed by RECIST. LTR was defined as partial response (PR) or complete response (CR) ≥ 24 months; STR was defined as PR/CR < 12 months followed by progressive disease (PD). PD-L1 IHC, tumor mutational burden (TMB), next generation sequencing (NGS), and whole exome sequencing (WES) results from subsets of pts were analyzed. High TMB was defined by harmonized TMB z-score ≥ 0 (≥ median TMB in each cohort: ≥ 7.9 for MSK, ≥ 10.5 for DFCI). Results: Among 3240 pts overall (MSK = 1536, DFCI = 1238, MDACC = 466), LTR was achieved in 267 (8.2%, 95% CI 7.3 to 9.2%) and STR was achieved in 213 (6.6%, 95% CI 5.7 to 7.5%), with similar rates from each site. 5-year overall survival (OS) was 83% among LTR and 20% among STR. In univariate analyses, non-squamous histology (non-SQ: odds ratio [OR] 2.13, p = 0.005), peripheral blood derived neutrophil to lymphocyte ratio (dNLR) < 3.0 (OR 2.15, p < 0.001), and high TMB (OR 2.25, p = 0.001) were associated with LTR compared to STR; high PD-L1 (PD-L1 ≥ 50%: OR 1.19, p = 0.494) was not. In multivariate analyses, non-SQ histology (OR 2.56, p = 0.047) and high TMB (OR 2.73, p = 0.001) remained independently associated with LTR over STR. Among LTR compared to patients with best response of PD, dNLR < 3.0 (OR 1.72, p = 0.030), high PD-L1 (OR 5.23, p < 0.001), and high TMB (OR 2.55, p = 0.001) associated with LTR. LTR showed deeper radiographic responses compared to STR (best response of -50% or greater: OR 3.88, p < 0.01). Among 1798 pts with NGS, pathogenic ARID1A alterations were numerically higher among LTR compared to STR, but this was not significant when accounting for multiple hypothesis testing (14% vs 2%, p = 0.022, q = 0.196). Among 73 pts with available WES, both clonal (p = 0.037) and subclonal TMB (p = 0.010) were significantly higher among LTR compared to STR. Conclusions: We report outcomes from > 10 years of advanced NSCLC pts treated with anti-PD(L)1 therapy in a large multicenter cohort, with ongoing response at 2 years associated with > 80% 5-year OS. High TMB was a strong independent predictor of LTR over STR. Non-squamous histology, low dNLR, and depth of response also correlate with LTR, while no individual genomic alterations clearly distinguish LTR. These features may assist in identifying pts more likely to derive durable benefit from anti-PD(L)1 therapy without treatment intensification.

Abstract 5462: Elevated creatine phosphokinase (CPK) as a strong predictor of aumolertinib (Au) treatment response in patients (pts) with advanced non-small cell lung cancer (NSCLC): post-hoc analysis of AENEAS

Abstract Background: In AENEAS trial (NCT03849768), first-line Au for EGFR-mutated, advanced NSCLC showed robust improvement in PFS over gefitinib (G). CPK elevation was the most common AE during Au treatment which may pose safety concerns. To evaluate the relationship between CPK elevation and Au efficacy, we performed a post-hoc analysis of AENEAS. Methods: AENEAS is a double-blind, randomized controlled phase III trial. Untreated advanced NSCLC pts with EGFR sensitizing mutations were assigned 1:1 to receive Au (110 mg QD) or G (250 mg QD). The primary endpoint was PFS. Secondary endpoints included ORR, DCR, DoR and DepOR. Data cutoff: Aug 1, 2021. Results: 37.9% (81/214) of pts receiving Au had CPK elevation, among whom the mPFS was 26.3 mos and was significantly longer (HR=0.45; 95% CI: 0.31-0.67; P<.0001) than that of the CPK-normal pts (133/214) at 13.9 mos. PFS benefits remained consistent across all prespecified subgroups. Also for all the secondary endpoints, CPK-elevated pts demonstrated significant benefits over CPK-normal pts (TABLE). Multivariable regression analysis revealed that CPK elevation was an independent predictor of prolonged PFS for pts receiving Au, with 54% reduced risk of progression or death for CPK-elevated pts compared with CPK-normal pts (HR=0.46; 95%CI: 0.31-0.68; P=.0001). Au demonstrated PFS benefits over G in both CPK-elevated pts (HR=0.40; 95% CI: 0.21-0.79; P=.0059) and CPK-normal pts (HR=0.63; 95% CI: 0.48-0.83; P=.0010), and the benefit was magnified in CPK-elevated pts. Further supported by post-hoc analysis of a phase 1/2 study (NCT02981108), PFS was also significantly prolonged in CPK-elevated pts receiving second or later line Au (17.7 vs 10.9 mos; HR=0.63; 95% CI: 0.46-0.87; P=.0049). Conclusion: Our study first revealed the predictive value of CPK elevation on improved treatment response of Au, which is of great significance to help guide medical care. Summary of Endpoints Elevated CPK(N=81) Normal CPK(N=133) PFS, months Median (95% CI) 26.3 (20.7-NA) 13.9 (12.4-19.8) HR (95% CI) 0.45 (0.31-0.67) P-value <0.0001 12-months PFS rate (95% CI) 84.9 (74.9-91.1) 59.4 (50.2-67.5) 24-months PFS rate (95% CI) 54.3 (42.4-64.7) 30.1 (21.9-38.8) DoR, months Median (95% CI) 23.5 (18.1-NA) 15.2 (10.2-19.2) HR (95% CI) 0.51 (0.33-0.79) P-value 0.0024 12-months DoR rate (95% CI) 77.7 (65.7-85.9) 55.8 (44.3-65.9) 24-months DoR rate (95% CI) 46.9 (33.7-59.0) 31.0 (20.9-41.6) ORR (95% CI), % 87.7 (78.5-93.9) 66.9 (58.2-74.8) OR (95% CI) 3.54 (1.64-7.64) P-value 0.0013 DCR (95% CI), % 98.8 (93.3-100.0) 89.5 (83.0-94.1) OR (95% CI) 9.59 (1.22-75.54) P-value 0.0318 DepOR, % Mean (Std) -50.5 (17.4) -42.0 (24.1) Range -100.0-3.6 -100.0-50.0 P-value 0.0105 Citation Format: Shun Lu, Chuan Li, Hong Jian, Xiaorong Dong, Jianhua Chen, Gongyan Chen, Yuping Sun, Yinghua Ji, Jiawei Wei, Si Sun, Zhenzhong Su, Qiu Sun, Hongying Wei, Qiong Wu. Elevated creatine phosphokinase (CPK) as a strong predictor of aumolertinib (Au) treatment response in patients (pts) with advanced non-small cell lung cancer (NSCLC): post-hoc analysis of AENEAS. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5462.

1030P Anlotinib plus docetaxel in the treatment of non-small cell lung cancer (NSCLC) after failure of previous immune checkpoint inhibitors (ICIs) therapy: Updated results from a pooled analysis of two phase II trials

ICIs are widely used in 1st -line or 2nd -line treatment of advanced NSCLC, but effective treatment after resistance to ICIs is still controversial. We previously reported some results of the pooled analysis of ALTER-L016 and ALTER-L018, which demonstrated that anlotinib plus docetaxel had encouraging efficacy and manageable toxicity in advanced NSCLC patients (pts) who had been pre-treated with ICIs. Here, we continued to update the efficacy and safety of the combination in the pooled analysis of ALTER-L016 and ALTER-L018. Efficacy and safety data from 2 multi-institutional, randomized, controlled comparative, phase II trials of 73 advanced NSCLC pts who had progressed after 1st-line platinum-based chemotherapy were pooled for this analysis. The studies shared similar dosing intervals and doses, pts were randomly allocated to receive anlotinib (10/12 mg QD from day 1 to 14 of a 21-day cycle) plus docetaxel (60/75 mg/m2 Q3W) (group A+D) or docetaxel (60/75 mg/m2 Q3W) only (group D). Safety assessments included adverse events (AEs), physical examination and clinical laboratory tests. As of 30 April, 2022, 73 pts were available for efficacy and safety analysis (demographics are shown in Table). The median (m) PFS was 5.20 months (m) (95%Cl: 2.96-7.44) vs 2.20 m (95%Cl: 1.06-3.34) in group A+D and group D, respectively (HR: 0.29; 95%Cl: 0.16-0.52, p<0.0001). The mOS has not been reached. For tumor response, the ORR was 34.90% vs 13.30% and the DCR was 93.02% vs 60.00% in group A+D and group D, respectively. The most common grade 3/4 TRAEs were neutropenia (5, 11.6%) and leukopenia (2, 4.7%) in group A+D, and dysphagia (1, 3.3%) in group D.Table: 1030PDemographicsExperimental (anlotinib + docetaxel) (n=43)Control (docetaxel) (n=30)Median age, years62 (31-74)60 (41-73)Age group, years, n (%)< 6018 (41.86)14 (46.67)≥ 6025 (58.14)16 (53.33)Sex, n (%)Men40 (93.02)24 (80.00)Women3 (6.98)6 (20.00)Disease stage, n (%)III5 (11.63)2 (6.67)IV38 (88.37)28 (93.33)ECOG PS, n (%)013 (30.23)9 (30.00)130 (69.77)21 (70.00)Histologic subtype, n (%)ADC20 (46.51)13 (43.33)Non-ADC23 (53.49)17 (56.67)Smoking history, n (%)Never smoker9 (20.93)10 (33.33)Current/ Former smoker34 (79.07)20 (66.67)Brain metastasis, n (%)Yes6 (13.95)4 (13.33)No37 (86.05)26 (86.67) Open table in a new tab Anlotinib plus docetaxel continued to show better clinical efficacy with manageable safety profile in advanced NSCLC pts who had been pre-treated with ICIs.

Gender and weight change, skeletal muscle index(SMI) change, and survival in advanced non-small cell lung cancer(NSCLC) patients(pts.) receiving platinum chemotherapy.

e24080 Background: Significantly longer OS has been reported in advanced NSCLC pts. who gained weight or maintained (skeletal muscle mass) SMI during treatment with platinum containing chemotherapy. None of these studies evaluated the relationship between OS and both weight and SMI. Sex specific distributions are described for cachexia and muscle wasting. Methods: The objective of this retrospective study was to evaluate the relationships between OS and both weight gain and SMI maintenance during front line chemotherapy in advanced NSCLC pts. Weight and SMI measurements(cm2/m2) were done at baseline and at 6, 12, &amp; 24 weeks. OS was estimated using the Kaplan-Meier method. The associations of weight and SMI with overall survival were assessed using Kaplan-Meier, log-rank test and proportional hazards regression. Results with p &lt; 0.05 were reported as significant. Results: Characteristics for the 88 patients were: median age – 64 years, women – 57%, caucasian – 68%, black – 25%, and adenocarcinoma histology – 63%. Weight gain (i.e., &gt; 0%) and &gt; 5% weight gain were observed in 50% and 11.3% of the patients, respectively. For all 88 patients the hazard ratio(HR) for OS in patients with &gt; 0% vs &lt; 0% weight change was 0.544 (p = 0.0164), and the HR for OS for weight &gt; 5% vs &lt; 5% was 0.469 (p = 0.099). The HR for OS in men for &gt; 0% vs &lt; 0% weight gain was 0.421(p = 0.031), and HR for OS &gt; 5% vs &lt; 5% weight gain was 0.421 (p = 0.031). The same analyses in women showed no significant differences. Increases in SMI &gt; 0% and &gt; 5% SMI were found in 48% and 35% of patients, respectively. Maintenance of SMI defined as &gt; - 1.3% was observed in 25% of pts. The HR for OS in men with SMI maintenance versus loss was 0.230 (p = 0.031), and the HR for OS in men with SMI increase &gt; 5% vs &lt; 5% was 0.219 (p = 0.0267). Neither SMI gain nor maintenance were significantly related to OS in the entire patient group or in women. Conclusions: In patients treated with first line platinum doublet, as a group there were no significant relationships between weight changes or SMI changes and OS. The observation that either weight gain or SMI maintenance was associated with longer OS in men only is based on data from a small number of patients. However, if larger studies show similar results, these findings could have implications for clinical and translational research in cachexia.

Association between immune-related adverse events and microbiome composition in patients with advanced non–small cell lung cancer treated with immunotherapy.

9036 Background: Despite immune-checkpoint inhibitors (ICI) achieving high response rates in patients (pts) with advanced non-small cell lung cancer (NSCLC), immune-related adverse events (irAE) remain an important therapeutic hurdle. The gut microbiome represents a novel prognostic marker of ICI response and early clinical evidence suggests that the microbiome may also regulate the development of irAE. We aimed to assess the association between irAE and the gut microbiome composition in advanced NSCLC pts amenable to ICI. Methods: In this study, we enrolled 464 pts from two independent cohorts (Montreal and Tokyo) with advanced NSCLC treated with ICI monotherapy or combination with chemotherapy. Fecal samples were collected prior to ICI initiation. Metagenomics microbiome profiling and 16S rRNA microbiome sequencing were performed for 81 pts and 133 pts respectively. The irAE were classified as CTCEA grade 0-1 (G0-1 irAE) and grade &gt; 2 (G2-5 irAE). Microbiome composition of both groups was represented using alpha diversity, beta diversity indexes and LEfSe relative abundances. Results: Median follow-up was 28.3 months (mos) and the incidence of G2-5 irAE was 25.1% in the Montreal cohort. For the Tokyo cohort, the median follow-up was 19.6 mos and 30.8% pts developed G2-5 irAE. First, in both cohorts, overall survival (OS) and progression-free survival (PFS) were significantly improved for pts with G2-5 irAE compared to G0-1 irAE (OS: HR: 1.71, p = 0.008 and PFS: HR: 1.65, p &lt; 0.001) and (OS: HR: 2.34, p = 0.001, and PFS: HR = 2.34, p = 0.006) respectively. Second, metagenomics analysis of 81 pts demonstrated a numerical decrease of the alpha diversity in terms of observed species in the G2-5 irAE. Dorea sp CAG 31, Anaerosporobacter mobilis, Butyricicococcus, and Enterococcus faecium were overrepresented in pts with G2-5 irAE. Conversely, Gordonibacter was increased in G0-1 irAE. Next, 16S rRNA profiling from the Tokyo cohort revealed an enrichment of Dorea, Butyricicococcus, and Eubacterium ventriosum in G2-5 irAE . Finally, we observed an enrichment in Dorea and Butyricicococcus in the pts with PFS &gt; 6 months, as observed in the G2-5 irAE group. Conclusions: IrAE correlated with clinical outcome and microbiome composition in two independent cohorts of pts with advanced NSCLC. These results prompt further research on the potential mechanism underling the role of the microbiome in the development of irAE.

High-dose icotinib in advanced lung adenocarcinoma(LUAD) patients harboring EGFR exon 21 L858R mutation: Real-world (RW) experience in a single center.

e21036 Background: Non-small cell lung cancer(NSCLC) patients(pts) with epidermal growth factor receptor (EGFR) exon 19 deletion have more benefit from EGFR-tyrosine kinase inhibitors(EGFR-TKIs) compared to pts with EGFR exon 21 L858R mutation. Icotinib, which is a first-generation EGFR-TKI had been approved for use in EGFR-positive advanced NSCLC pts. A phase II trial(INCREASE trial) showed that high-dose icotinib 250mg tid(ico250) can effectively prolong the progression-free survival(PFS) of NSCLC pts with exon 21 L858R mutation without increased toxicity. However, the RW evidence is lacking. Methods: In this single-center, single-arm study, data were retrospectively collected from China-Japan Friendship Hospital. Pts with advanced LUAD, harboring EGFR exon 21 L858R mutation, and who received ico250 for more than 20 days without chemotherapy or immunotherapy were reviewed. Clinical data were analyzed for PFS, objective response rate(ORR), disease control rate(DCR), overall survival(OS), duration of treatment(DoT) and adverse events(AEs). Survival factors were evaluated by univariate and multivariate Cox regression analysis. Results: In total 40 pts(14M,26F; median age 67[46-86]; smoker:20.0%; ECOG performance status 0-1/2-3: 33/7) who received ico250 between 4/2019-11/2021 were analyzed. The median line of pre-ico therapies was 1(range 0-2). At the cut-off day, 29(72.5%) pts had discontinued ico250, and 7(17.5%) pts died. Overall, ORR was 30.0%, DCR was 80.0%, median DoT was 8.0mos (95%CI, 3.4-12.6), median PFS was 12.9mos (95%CI, 8.2-17.6) and median OS was not reached. The univariate and multivariate analysis showed that there was no significant and independent factor associated with PFS(all P&gt; 0.05). 30(75.0%) pts experienced AEs, while the most common AEs were rash(24,60.0%), dry skin(9,22.5%), paronychia(8,20.0%) and diarrhea(6,15.0%). Grade 3/4 AEs in 6(15.0%) pts included AST/ALT elevation(3,7.5%), rash(2,5%), diarrhea(1,2.5%) and mucositis(1,2.5%)(1 suffered both rash and mucositis). 5(12.5%) pts discontinued high-dose icotinib due to AEs. Conclusions: These data add to the RW evidence that the efficacy and tolerability of ico250 in advanced LUAD pts harboring EGFR exon 21 L858R mutation. The efficacy results are consistent with the previous INCREASE trial. High-dose icotinib could be considered whatever the previous treatment and basic characteristics of LUAD pts with exon 21 L858R mutation. However, the higher incidence of grade3/4 AEs deserves special attention.

A phase Ib/II study of AK112, a PD-1/VEGF bispecific antibody, as first- or second-line therapy for advanced non–small cell lung cancer (NSCLC).

9040 Background: Besides the well-known antiangiogenic effects, anti-VEGF agents also modulate the tumor immune micro-environment, leading to synergic anti-tumor effects. AK112 is a humanized IgG1 bispecific antibody against PD-1 and VEGF. Here, we reported results of an ongoing phase Ib/II trial of AK112 in advanced NSCLC pts. Methods: Pts with stage IIIB/IIIC/IV NSCLC, ECOG PS 0-1 and negative oncogenic drivers were enrolled and given AK112 (10 mg/kg Q3W, 20 mg/kg Q2W, 20 mg/kg Q3W or 30 mg/kg Q3W) intravenously. The primary endpoints were ORR per RECIST v1.1 and safety. Results: At data cutoff (January 5, 2022), 94 pts were enrolled: median age 66.0 years (range: 48-75), PS 1 90.4%, male 85.1%, non-squamous 48.9%, PD-L1 positive (TPS ≥1%) 70.2% and treatment-naïve 84.0%. Of 83 pts evaluable for efficacy, ORR (unconfirmed, similarly hereinafter) and DCR were 22.2%/88.9%, 44.0%/92.0%, 37.9%/93.1% and 100%/100% at doses of 10 mg/kg Q3W, 20 mg/kg Q2W, 20 mg/kg Q3W and 30 mg/kg Q3W, respectively. When doses of AK112 &gt; 10mg/kg Q3W, ORR and DCR were 42.9% (24/56) and 92.9% (52/56) in 56 evaluable pts, 56.3% (18/32) and 100% (32/32) in pts with TPS≥1% at 1st line setting, and 23.5% (4/17) and 76.5% (13/17) in pts with PD-L1 TPS &lt; 1%, respectively. Grade≥3 treatment-related adverse events (TRAEs) occurred in 10.6% (10/94) pts, in which the most common event (occurring in &gt; 1 pt) was pneumonia (2.1%, 2/94). No TRAEs led to permanent treatment discontinuation. Most frequent TRAEs (incidence ≥10%) were proteinuria (17.0%), hypertension (16.0%), lipase increase (12.8%), alanine aminotransferase increase (12.8%), blood urea increase (10.6%), apolipoprotein E increase (10.6%) and hyperglycaemia (10.6%). No significant difference in the incidences of TRAEs were observed between non-squamous and squamous pts. Conclusions: In advanced NSCLC, AK112 was well-tolerated and presented remarkable anti-tumor efficacy. Further phase III studies are planned to validate the findings of this study. Clinical trial information: NCT04900363.

Residual of circulating tumor DNA (ctDNA) indicated therapeutic efficacy of sintilimab plus docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC).

e21207 Background: The synergetic effect of ICIs plus chemotherapy has been demonstrated in first line setting for patients with advanced NSCLC. As previously reported, sintilimab plus docetaxel in advanced Chinese NSCLC pts who had failed first-line chemotherapy showed encouraging efficacy and tolerable safety profile. This exploratory study aims to investigate putative biomarker(s) predicting therapeutic response and long-term outcome for eligible patients. Methods: Advanced NSCLC pts who had failed standard platinum doublet without receiving any ICIs before would receive docetaxel (75mg/m2, day 1) plus sintilimab (200mg, day 3) every 3 weeks for 4-6 cycles followed by sintilimab maintenance until disease progression, unacceptable toxicity, or up to 2 years. Thirty-nine eligible patients received comprehensive genomic profiling of circulating tumor DNA (ctDNA) via a 448-gene panel before treatment. ctDNA from twenty-three patients were dynamically assessed after two courses (at 6th week). Eventually, 22 patients were enrolled into analysis, one patient was lost. White blood cells were used to filter germline variants from ctDNA sequencing data. Results: Of 22 patients with paired ctDNA profiling results at 6th week, 11 patients (50%) were defined as ctDNA residual due to presence of ≥2 somatic variants; Another 11 patients (50%) who had ≤1 somatic variant were defined as non-ctDNA residual. Significant difference of best objective response rate (ORR) (63.64% vs 0%, P=0.0039, two-sided Fisher’s Exact Testing for non-ctDNA residual vs ctDNA residual patients) was observed between these two populations. And numerically higher disease control rate (DCR) was seen in non-ctDNA residual patients (100% vs 63.64%, non-ctDNA residual vs ctDNA residual). Further, patients with ctDNA residual after 2 courses of sintilimab plus docetaxel (at 6th week) displayed higher risk of disease progression [Hazard Ratio (95%CI), 9.91(2.09-46.97), P=0.0038] and inferior prognosis (median PFS, ctDNA residual vs non-ctDNA residual, 3.0 months vs NR, P=0.0007). In addition, mutations of EGFR and LRP1B were enriched in ctDNA residual group. Especially, LRP1B gene mutations associated with shorter PFS period, which should be further investigated. Conclusions: Residual of ctDNA at 6th week was able to indicate inferior response to sintilimab plus docetaxel in patients with previously treated advanced NSCLC. Further validation of ctDNA residual as a robust predictive biomarker is warranted. [Table: see text]

Network meta-analysis (NMA) of immuno-oncology (IO) monotherapy as first-line (1L) treatments (txs) for advanced non-small cell lung cancer (NSCLC) with PD-L1 expression ≥50%.

e21091 Background: For advanced NSCLC patients (pts) with high (≥50%) PD-L1 expression, effective IO mono options with survival benefits are approved (pembrolizumab mono, current standard of care) and emerging (cemiplimab). In a recent Phase 3 trial, cemiplimab, a high-affinity, highly potent human PD-1 inhibitor approved for tx of advanced cutaneous squamous cell carcinoma, demonstrated significantly improved overall survival (OS) and progression-free survival (PFS) vs chemotherapy (CT) in advanced NSCLC pts with PD-L1 ≥50%. A systematic literature review and NMA were conducted to identify/compare the efficacy/safety from randomized controlled trials (RCTs) for cemiplimab vs pembrolizumab or other IO mono published 2010–19. Methods: Relevant RCTs were identified by searching Embase, MEDLINE, Cochrane, and conference proceedings with predefined search strategies according to ISPOR, NICE, and PRISMA guidelines. An NMA with time-varying hazard ratios (HRs) was performed for OS and PFS. Analyses were conducted for objective response rate (ORR), Grade (G) 3–5 all-cause adverse events (AE), G3–5 immune-mediated AE (IMAE) and discontinuation due to AEs (DAE). Fixed-effect models were used due to limited evidence. Results with standard constant HRs and various sensitivity analyses were conducted to account for differences in RCT designs and other txs. Results: The feasibility assessment determined that EMPOWER-Lung 1, KEYNOTE-024, and KEYNOTE-042 trials were eligible. IMpower110 was excluded since an incompatible PD-L1 assay (SP142) was used for pt selection. For 1L advanced NSCLC with PD-L1 ≥50%, cemiplimab was associated with significantly greater PFS and ORR, and comparable OS, G3–5 AEs, IMAEs, and all-cause DAEs vs pembrolizumab (Table). At 2 yrs, numerically more pts receiving cemiplimab vs pembrolizumab were alive (59% vs 49%) and significantly more were alive w/o progression (37% vs 18%). Conclusions: In advanced NSCLC pts with PD-L1 ≥50%, cemiplimab mono demonstrated significant improvements in PFS and ORR, and comparable OS, safety/tolerability vs pembrolizumab.[Table: see text]

Interim results of viagenpumatucel-L (HS-110) plus nivolumab in previously treated patients (pts) with advanced non-small cell lung cancer (NSCLC) in two treatment settings.

9100 Background: Viagenpumatucel-L (HS-110) is an allogeneic cell therapy derived from a human lung adenocarcinoma cell line incorporating multiple cancer testis antigens and transfected with a gp96-Ig fusion protein. Methods: We report interim results of cohort A (previously treated pts who had not received a checkpoint inhibitor [CPI]) and cohort B (pts who progressed after CPI treatment) in an ongoing phase 2 trial evaluating HS-110 plus nivolumab (NIVO) in advanced NSCLC pts (NCT02439450). Pts received HS-110 (1×107 cells) intradermally QW for 18 wk and NIVO Q2W until tumor progression. Stratified analyses were performed by injection site reaction (ISR), yes (+) or no (–); baseline blood tumor mutational burden (bTMB), bTMB-L (&lt;10 mutations/ megabase [mut/Mb]) or bTMB-H (≥10 mut/Mb) by FoundationACT test; and baseline PD-L1 expression, – (&lt;1%) or + (≥1%). Results: As shown in the Table, median progression-free survival (PFS) in cohort A (n=47) was 1.8 mo (95% CI 1.8-7.8) and median overall survival (OS) was 24.6 mo (95% CI 11.7-36.0) after a median follow-up (MFU) of 19.5 mo. We observed significantly longer PFS and OS in ISR+ pts (hazard ratio [HR] 0.43, p=0.01; HR 0.23, p&lt;0.001) and longer OS in PD-L1+ pts (HR 0.25, p=0.02). In cohort B (n=68), median PFS was 2.8 mo (1.8-3.9) and median OS was 11.9 mo (9.7-16.3) after a MFU of 11.9 mo. We observed significantly longer OS in ISR+ pts (HR 0.48, p=0.03) and a trend toward extended OS in bTMB-L pts (HR 0.58, p=0.20). HS-110 TEAEs were reported in 21 (44.7%) pts in cohort A and 18 (26.5%) pts in cohort B. TEAEs in &gt;5% of pts included fatigue, maculopapular rash, nausea, diarrhea, and pruritus. Few HS-110–related TEAEs led to discontinuation of treatment [cohort A, 5 (10.6%); cohort B, 3 (4.4%)], and no serious AEs were considered related to HS-110. Conclusions: HS-110 was well tolerated when administered in combination with NIVO. In previously treated pts with advanced NSCLC, we observed (1) significantly longer PFS and OS in ISR+ pts in both CPI naïve and CPI progressor cohorts; (2) significantly longer OS in PD-L1+ patients in the CPI naïve cohort; and (3) a trend of improved OS in bTMB-L pts in the CPI progressor cohort. Further clinical evaluation of HS-110 is warranted in both CPI naïve and CPI progressor NSCLC patients. Clinical trial information: NCT02439450. [Table: see text]

Anlotinib plus docetaxel versus docetaxel as second-line treatment for advanced non-small cell lung cancer (NSCLC): Updated results from a phase I/II study.

e21055 Background: Second-line chemotherapy alone, such as docetaxel, is standard of care for patients (pts) with advanced NSCLC, but the efficacy is poor. Anti-angiogenic drugs plus chemotherapy had shown to significantly prolong progression-free survival (PFS) in advanced NSCLC (REVEL and LUME-LUNG1). The REVEL trial had demonstrated that East Asian pts with advanced NSCLC receiving docetaxel (60 mg/m2, not 75mg/m2) and ramucirumab had a better safety profile. Anlotinib, a novel oral multitarget tyrosine kinase inhibitor, significantly improved PFS and overall survival (OS) of advanced NSCLC in the ALTER0303 trial. In the phase I study, 10mg (QD, d1 to 14 of a 21-day cycle) was identified as the maximum tolerated dose (MTD) of anlotinib when combined with docetaxel (60mg/m2) by a 3+3 dose de-escalation exploration. Here, we presented the updated efficacy and safety of anlotinib plus docetaxel versus docetaxel as second-line treatment for driver-negative advanced NSCLC in the phase II study. Methods: This open-label, multicenter, randomized phase II study enrolled advanced NSCLC pts who had progressed after first-line platinum-based chemotherapy, without sensitizing EGFR/ALK/ROS1 alterations, and with ECOG PS 0-1. Eligible pts were randomized 2:1 to receive anlotinib (10mg, p.o, QD, d1 to 14 of a 21-day cycle) plus docetaxel (60mg/m2, q3w, 4-6 cycles) (A+D arm) or docetaxel (60mg/m2, q3w, 4-6 cycles) alone (D arm) until disease progression or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included the objective response rate (ORR), the disease control rate (DCR), OS and safety. Results: From Jun. 2019 to Dec. 2020, 36 pts were enrolled, 24 pts (median age: 63.0, squamous cell carcinoma: 50.0%, ECOG PS 1: 87.5%) in the A+D arm and 12 pts (median age: 60.0, squamous cell carcinoma: 50.0%, ECOG PS 1: 83.3%) in the D arm. As of Jan. 20, 2021, the median PFS were 6.2 months (95% Cl: 0.00-12.82) in the A+D arm vs 1.4 months (95% Cl: 0.71-2.09) in the D arm (HR: 0.30; 95% Cl: 0.11-0.78, p = 0.007), which remain immature because of the shorter follow-up time. The median OS was not reached. For tumor response, 32 pts were evaluable. The ORR was 27.3% in the A+D arm vs 0% in the D arm (p = 0.142), and the A+D arm showed a significantly higher DCR than the D arm (100.0% vs 50.0%, p = 0.001). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 33.3% (A+D arm) and 0.0% (D arm). The most commonly reported grade 3/4 TRAEs in the A+D arm included neutropenia (8.3%, 2/24), leukopenia (8.3%, 2/24), oral mucositis (8.3%, 2/24) and hypertension (8.3%, 2/24). No grade 5 TRAEs or deaths were observed. Conclusions: Anlotinib plus docetaxel continues to show the better clinical benefit as second-line treatment for driver-negative advanced NSCLC. The safety profile was manageable and consistent with previously reported studies. The longer follow-up time is required. Clinical trial information: NCT03726736.