Non-squamous Non-small Cell Lung Carcinoma Research Articles

Adagrasib in KRYSTAL-12has Broken the KRAS G12C Enigma Code in Non-Small Cell Lung Carcinoma.

Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C-mutant non-small cell lung carcinoma (NSCLC) accounts for approximately 10-13% of advanced nonsquamous NSCLC cases in Western populations, presenting a significant therapeutic challenge owing to the difficulty of directly targeting KRAS. Adagrasib, an oral small-molecule covalent inhibitor, irreversibly and selectively targets KRASG12C in its inactive state. It received accelerated Food and Drug Administration (FDA) approval on December 12, 2022, following the KRYSTAL-1 Phase II trial. The Phase III KRYSTAL-12 trial demonstrated that adagrasib significantly improved median progression-free survival (mPFS) compared with docetaxel (HR, 0.58; 95% CI: 0.45-0.76; P<0.0001) and increased the intracranial objective response rate (ORR) to 40% in the central nervous system (CNS) evaluable population. This paper evaluates the clinical efficacy of adagrasib in KRAS G12C-mutated advanced NSCLC discussing its potential advantages over other inhibitors such as sotorasib. Despite not reaching the 6-month mPFS benchmark, adagrasib offers significant clinical benefits, particularly for the management of CNS metastases. In this pros and cons debate, we argue that adagrasib has broken the KRAS G12C enigma code in NSCLC.

Comparison and performance of three plasma next-generation sequencing assays versus tissue testing for the detection of actionable driver mutations in advanced non-squamous non-small cell lung carcinoma.

e20018 Background: Liquid biopsy (LB) is a useful tool for the detection of actionable mutations in advanced non-squamous non-small cell lung cancer (NS-NSCLC) at progression. However, the clinical benefits of integrating both LB and tissue biopsy (TB)-based genomic profiling at diagnosis of NS-NSCLC remain uncertain. Methods: We tested three commercially available next-generation sequencing (NGS) gene panel assays in circulating cell-free DNA (cfDNA) using replicate sets of 85 LB samples from advanced NS-NSCLC patients at baseline and compared the results with matched TB for the detection of tier IA/B (AMP/ASCO/CAP classification) alterations. We used methylation testing of cfDNA to assess the tumor fraction (TF). We correlated molecular data with clinico-pathological features and follow-up data. Results: All TB-based NGS results were interpretable. 5 LB-based NGS results for one assay were not performed due to the material exhaustion. Tier IA/B gene alteration was detected by LB-based NGS and TB-based NGS in 18 to 23 (21 to 27%) patients and in 35 (41%) patients, respectively. The positive percent agreement of each LB-based NGS assay method compared with TB-based NGS assay ranged from 51% to 68%. The incremental add provided by first LB-based NGS ranged from 0 to 23% versus 25 to 45% for first TB-based NGS, depending on the LB-based NGS assay. It includes one EGFR uncommon mutation, 9 MET amplifications and 2 HER2 amplifications detected by LB-based NGS assays that were not detected by TB-based NGS. Overall agreement between the three LB-based NGS assays was 44%. Hybrid-capture based assay detects 14 MET/HER2 CNVs, two METex14 skipping mutation and two ALK fusions that were not detected by amplicon-based assay. Amplicon-based assay detects one uncommon EGFR mutation, one KRAS non-G12C and one ALK fusion that were not detected by hybrid-capture based assay. 64 LB samples were tested for cfDNA methylation. Positive predictive value and negative predictive value of the detection of TF by cfDNA methylation profiling was 90% and 92%, respectively. The only false-negative result of TF evaluation by cfDNA methylation profiling was observed for a variant with a cfDNA VAF &lt; 1%. Correlation analyses with clinicopathological data are ongoing. Conclusions: While concordance with tissue is relatively high, the incremental add provided by LB-based NGS at diagnosis of advanced NS-NSCLC compared to TB-based NGS is limited and greatly varies according to the sequencing method used. Thus, LB-based NGS at diagnosis of NSCLC can be used as a complement of TB-based NGS or as an alternative when tissue is not available.

Anlotinib in Chinese patients aged ≥70 years with advanced non-squamous non-small cell lung cancer without prior chemotherapy: a multicenter, single-arm pilot trial.

Based on pharmacoeconomics, drug availability and actual treatment, optimal treatment regimens for Chinese non-small-cell lung carcinoma (NSCLC) patients over 70 years old are needed. This multicenter, single-arm pilot trial enrolled patients with advanced non-squamous NSCLC who refused systemic chemotherapy. Eligible patients received anlotinib (12 mg/day, d1-14, Q3W) until disease progression, intolerant toxicities, or withdrawal from the study. The primary endpoint was progression-free survival (PFS). Forty-nine patients were screened between January 2019 and September 2021, of whom 40 patients were eligible. The median age was 76 years. With a median follow-up period of 16.20 (95% CI: 8.77, 25.10) months, the median PFS was 5.45 months (95% CI: 3.52-9.23) and the median overall survival was 10.32 months (95% CI: 6.44-12.78). Three patients achieved a partial response and 34 had stable disease, with an objective response rate of 7.5% and a disease control rate of 92.5%. Thirty-three (82.5%; 33/40) patients reported treatment-related adverse events (TRAEs) of any grade, and the incidence rate of grade ≥3 TRAEs was 35% (14/40). The most common grade ≥3 TRAEs were hypertension (4/40; 10.0%), hand-foot syndrome (3/40; 7.5%), and proteinuria (2/40; 5.0%). Anlotinib treatment was feasible and safe in Chinese elderly patients with advanced non-squamous NSCLC who did not receive any systemic chemotherapy.

STK11/LKB1 alterations worsen the poor prognosis of KRAS mutated early-stage non-squamous non-small cell lung carcinoma, results based on the phase 2 IFCT TASTE trial

BackgroundSTK11/LKB1 mutations have been associated with primary resistance to PD-1 axis inhibitors and poor prognosis in advanced KRAS-mutant lung adenocarcinoma. This study aimed to assess the prognostic significance of STK11/LKB1 alterations in localized non-squamous non-small cell lung carcinoma (non-sq NSCLC). Patients and methodsSurgical samples from patients undergoing complete resection for stage IIa, IIb, or IIIa (N2 excluded) non-sq NSCLC in the randomized adjuvant phase II trial (NCT00775385 IFCT-1801 TASTE trial) were examined. Patients received either standard chemotherapy (Pemetrexed Cisplatin) or personalized treatment based on EGFR mutation (Erlotinib) and ERCC1 expression. Tumor molecular profiles were analyzed using targeted NGS and correlated with overall survival (OS) and disease-free survival (DFS), adjusting for relevant clinical variables. Additionally, interactions between treatment groups and molecular alterations on OS, PD-L1 expression, and tumor-circulating DNA in post-operative plasma samples were evaluated. ResultsAmong 134 patients (predominantly male smokers with adenocarcinoma), KRAS mutations were associated with shorter DFS (HR: 1.95, 95 % CI: 1.1–3.4, p = 0.02) and OS (HR: 2.32, 95 % CI: 1.2–4.6, p = 0.014). Isolated STK11/LKB1 mutations (n = 18) did not significantly impact DFS or OS. However, within KRAS-mutated samples (n = 53), patients with concurrent STK11/LKB1 mutations (n = 10) exhibited significantly shorter DFS (HR: 3.85, CI: 1.5–10.2, p = 0.006) and a trend towards shorter OS (HR: 1.80, CI: 0.6–5.3, p = 0.28). No associations were found between PD-L1 expression, other gene mutations, progression-free survival (PFS), or OS. ConclusionThis analysis reinforces KRAS mutations as predictive factors for relapse and poor survival in localized non-sq NSCLC. Furthermore, the presence of concomitant STK11/LKB1 mutations exacerbated the prognosis within the KRAS-mutated subset. These findings emphasize the clinical relevance of these molecular markers and their potential impact on treatment strategies in non-sq NSCLC.

EGFR assessment using next generation sequencing as a reflex testing on surgically resected non-squamous non-small cell lung carcinoma.

8539 Background: EGFR status assessment is mandatory in early stage (IB-IIIA) non-squamous non-small cell lung carcinoma (NS-NSCLC), but whether NGS methods should be used as reflex testing for this evaluation in daily practice is controversial. However, co-occuring mutations, notably TP53 mutations, may have an impact on tumor behavior and prognosis, and so, on future adjuvant therapeutic strategies. Methods: EGFR mutations were assessed prospectively using NGS (Oncomine Precision Assay genes panel) in 720 NS-NSCLC surgically resected between January 2021 and September 2022 in a single institution (LPCE, Nice, France). PD-L1 expression was evaluated in all tumors. Disease free survival (DFS) analysis was available in 675/720 (94%) patients. Results: EGFR mutations were detected in 83/720 (11.5%) cases. A common non-compound EGFR mutation (L858R or del19) was observed in 62/83 (75%) cases. 12/83 (14%) and 9/83 (11%) tumors had a rare non-compound and compound EGFR mutations, respectively. 40/83 (48%) has a co-occuring mutation, including a TP53 (30/40; 75%) mutation, mainly in exon 5, 7 or 8. EGFR/TP53 mutated tumors were significantly associated with higher PD-L1 expression compared to EGFR mutated tumors. A significant correlation was noted between worse DFS and the detection of a mutation in EGFR exon 18 mutation, as well as the detection of a co-mutation in TP53 exon 7 and in MET exon 14. Conclusions: Genomic alteration should be systematically evaluated using an NGS reflex testing in surgically resected NS-NSCLC, since future adjuvant therapeutic decision making may consider the presence of compound EGFR mutations as well as co-occuring mutations in other genes, especially in TP53.

A Real-World Experience from a Single Center (LPCE, Nice, France) Highlights the Urgent Need to Abandon Immunohistochemistry for ROS1 Rearrangement Screening of Advanced Non-Squamous Non-Small Cell Lung Cancer.

The detection of ROS1 rearrangements in metastatic non-squamous non-small cell lung carcinoma (NS-NSCLC) permits administration of efficient targeted therapy. Detection is based on a testing algorithm associated with ROS1 immunohistochemistry (IHC) screening followed by ROS1 FISH and/or next generation sequencing (NGS) to confirm positivity. However, (i) ROS1 rearrangements are rare (1-2% of NS-NSCLC), (ii) the specificity of ROS1 IHC is not optimal, and (iii) ROS1 FISH is not widely available, making this algorithm challenging to interpret time-consuming. We evaluated RNA NGS, which was used as reflex testing for ROS1 rearrangements in NS-NSCLC with the aim of replacing ROS1 IHC as a screening method. ROS1 IHC and RNA NGS were prospectively performed in 810 NS-NSCLC. Positive results were analyzed by ROS1 FISH. ROS1 IHC was positive in 36/810 (4.4%) cases that showed variable staining intensity while NGS detected ROS1 rearrangements in 16/810 (1.9%) cases. ROS1 FISH was positive in 15/810 (1.8%) of ROS1 IHC positive cases and in all positive ROS1 NGS cases. Obtaining both ROS1 IHC and ROS1 FISH reports took an average of 6 days, while obtaining ROS1 IHC and RNA NGS reports took an average of 3 days. These results showed that systematic screening for the ROS1 status using IHC must be replaced by NGS reflex testing.

Molecular Profiling in Non-Squamous Non-Small Cell Lung Carcinoma: Towards a Switch to Next-Generation Sequencing Reflex Testing.

Molecular diagnosis of lung cancer is a constantly evolving field thanks to major advances in precision oncology. The wide range of actionable molecular alterations in non-squamous non-small cell lung carcinoma (NS-NSCLC) and the multiplicity of mechanisms of resistance to treatment resulted in the need for repeated testing to establish an accurate molecular diagnosis, as well as to track disease evolution over time. While assessing the increasing complexity of the molecular composition of tumors at baseline, as well as over time, has become increasingly challenging, the emergence and implementation of next-generation sequencing (NGS) testing has extensively facilitated molecular profiling in NS-NSCLC. In this review, we discuss recent developments in the molecular profiling of NS-NSCLC and how NGS addresses current needs, as well as how it can be implemented to address future challenges in the management of NS-NSCLC.

EP02.04-010 Clinical Outcomes After Neoadjuvant Tislelizumab plus Chemotherapy in Resectable Stage IIIA-B NSCLC: A Retrospective Study

Tislelizumab combined with chemotherapy was approved for first-line treatment of advanced squamous cell lung carcinoma and non-squamous non-small cell lung carcinoma in China. This study aimed to evaluate the efficacy of neoadjuvant Tislelizumab plus chemotherapy in resectable stage IIIA-B NSCLC in a real-world setting.

EP11.01-005 Ultra-Fast Gene Fusion Assessment as a Reflex Testing in Daily Clinical Practice for Advanced Non-small Cell Lung Cancer Patients

There is an urgent need to improve the broad molecular profiling of advanced non-squamous non-small cell lung carcinoma (NS-NSCLC) patients, notably for a rapid assessment of multiple genomic alterations.

A phase 1 multiple-ascending dose study to evaluate the safety and tolerability of XmAb23104 (PD-1 x ICOS) in subjects with selected advanced solid tumors (DUET-3).

2604 Background: XmAb23104 is a bispecific antibody targeting T cells that simultaneously express PD-1, an immune checkpoint, and ICOS, a costimulatory molecule expressed after T cell activation. DUET-3 is a Phase 1, first-in-human, dose-escalation and expansion study in subjects with advanced solid tumors, designed to assess safety, tolerability and to identify the maximum tolerated dose (MTD) of XmAb23104. Secondary objectives are to assess pharmacokinetics (PK), immunogenicity, and preliminary anti-tumor activity. We report preliminary data from the completed dose-escalation phase. Methods: A 3+3 monotherapy dose escalation with 9 dose levels from 0.002 to 15 mg/kg has been completed. Subjects with measurable disease who progressed on prior standard therapy were eligible. A minimum 6-week washout from prior pembrolizumab was required. XmAb23104 was administered biweekly and RECIST 1.1 assessment was performed every 8 weeks. Results: Sixty-two subjects were treated in escalation at doses up to 15 mg/kg; no dose-limiting toxicities were observed and an MTD was not reached. These subjects had advanced disease, 92% were Stage IV at screening, the median number of prior therapies was 3, and 37% had previous checkpoint therapy. Thirty-seven subjects (59.7%) experienced a treatment-related adverse event (TRAE); the most common were diarrhea (9.7%), decreased appetite (9.7%), and fatigue (9.7%). The majority of TRAEs were Grades 1 or 2, with 6 subjects (9.7%) having a Grade 3 or higher TRAE. Thirteen immunotherapy-related adverse events (irAEs) occurred in 8 subjects; no individual irAE occurred in more than 1 subject. Most irAEs were mild (Grades 1 and 2) with 1 Grade 3 pruritus and 1 asymptomatic Grade 4 lipase elevation. Partial responses were observed in 3 subjects (sarcoma; prior PD-1 head and neck squamous cell carcinoma [HNSCC] and renal cell carcinoma [RCC]), and stable disease &gt; 12 months was observed in 2 subjects with colorectal cancer (CRC; 1 MSS and 1 MSI-H). A dose of 10 mg/kg was selected after consideration of PK, safety, and clinical activity data in consultation with the investigators and continues to be evaluated in the expansion part of the study. Conclusions: The dose escalation part of this study indicates XmAb23104 was generally well tolerated at doses up to 15 mg/kg and has shown clinical activity in subjects with advanced solid tumors. CTLA4 blockade has been found to increase the frequency of ICOS-expressing T cells in prostate cancer, bladder cancer, melanoma, and hepatocellular cancer (Chen, 2009; Liakou, 2008; Wei, 2017) and may be applicable to other immunogenic tumor types. XmAb23104 is currently being studied alone or in combination with ipilimumab in expansion in non-squamous non-small cell lung carcinoma, melanoma, CRC, undifferentiated pleomorphic sarcoma, HNSCC, and RCC. Clinical trial information: NCT03752398.

A phase II study (TACTI-002) in first-line metastatic non–small cell lung carcinoma investigating eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab: Updated results from a PD-L1 unselected population.

9003 Background: Eftilagimod alpha (E) is a soluble LAG-3 protein binding to a subset of MHC class II molecules to mediate antigen presenting cell (APC)/CD8 T-cell activation. Stimulation of the APCs and subsequent T cell recruitment with E may lead to stronger anti-tumor responses than observed with pembrolizumab (P) alone. We hereby report results of the extended first-line non-small cell lung carcinoma (NSCLC) cohort of the TACTI-002 (“Two ACTive Immunotherapies”) phase II trial. Methods: Pts with untreated metastatic NSCLC, unselected for PD-L1 expression were recruited. Objective response rate (ORR) by iRECIST was the primary endpoint (EP) and secondary EPs include ORR by RECIST 1.1, tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS) and exploratory biomarker. Pts received 30 mg E SC q2w for 8 cycles (1 cycle= 3 weeks) and then q3w for up to 1 year with P (200 mg IV q3w for up to 2 years). Imaging was done every 8 weeks. PD-L1 was assessed centrally. This has been approved by relevant CAs, ECs, and IRBs. Results: From Mar 2019 to Nov 2021 114 pts were enrolled. Median age was 67 years (44-85) and 74% were male. ECOG PS was 0 and 1 in 37% and 63% of pts, respectively. Pts presented squamous (35%) or non-squamous (62%) NSCLC with 88% of pts at stage IV at the time of study entry. All PD-L1 subgroups were represented (Table). Pts received median 6.0 (range 1–35) P and 7.0 (1-22) E administrations. 19 (17%) pts discontinued treatment due to adverse events (AEs). The most common (≥15%) AEs were dyspnea (33%), asthenia (30%), decreased appetite (22%), cough (20%), anemia (20%), fatigue (19%), pruritus (18%), constipation (17%) and diarrhea (15%). At data cut-off (Jan 2022), 75 pts with a minimum follow-up of 6 months were evaluated for efficacy. ORR (iRECIST) was 37.3% in the ITT and 41.8%% in the evaluable pts assessed by local read. DCR 73.3% was reported. Response rate for squamous and non-squamous pathology were 33.3 % and 40.3 %, respectively. Results according to RECIST 1.1 were comparable. Responses were observed in all PD-L1 subgroups (Table). 24/28 (86%) responses were already confirmed while median duration of response was not yet reached (5 events). Conclusions: E + P is safe and shows encouraging antitumor activity in first-line metastatic NSCLC patients unselected for PD-L1, warranting further investigation. Clinical trial information: NCT03625323. [Table: see text]

Setting Up an Ultra-Fast Next-Generation Sequencing Approach as Reflex Testing at Diagnosis of Non-Squamous Non-Small Cell Lung Cancer; Experience of a Single Center (LPCE, Nice, France).

Simple SummaryDue to the increase of molecular biomarkers to be characterized to tailor therapeutic strategies for non-squamous non-small cell lung carcinoma (NS-NSCLC), it is now more and more challenging to evaluate these biomarkers using sequential analyses. We report here our experience concerning the development of an optimal workflow for genomic alteration assessment as reflex testing in routine clinical practice at diagnosis for NS-NSCLC patients by using an ultra-fast-next generation sequencing (NGS) approach. The analytical validation of the NGS workflow demonstrated 100% concordance with the gold standard methods. Only few cases failed for DNA/RNA NGS results. The mean turnaround time (TAT) was 72 h (ranging from 48 to 96 h). An ultra-fast NGS technique can maximize the management of the sample workflow in thoracic oncology to obtain the molecular biology results in an appropriate TAT, even when only a small amount of nucleic acids is available.The number of genomic alterations required for targeted therapy of non-squamous non-small cell lung cancer (NS-NSCLC) patients has increased and become more complex these last few years. These molecular abnormalities lead to treatment that provides improvement in overall survival for certain patients. However, these treated tumors inexorably develop mechanisms of resistance, some of which can be targeted with new therapies. The characterization of the genomic alterations needs to be performed in a short turnaround time (TAT), as indicated by the international guidelines. The origin of the tissue biopsies used for the analyses is diverse, but their size is progressively decreasing due to the development of less invasive methods. In this respect, the pathologists are facing a number of different challenges requiring them to set up efficient molecular technologies while maintaining a strategy that allows rapid diagnosis. We report here our experience concerning the development of an optimal workflow for genomic alteration assessment as reflex testing in routine clinical practice at diagnosis for NS-NSCLC patients by using an ultra-fast-next generation sequencing approach (Ion Torrent Genexus Sequencer, Thermo Fisher Scientific). We show that the molecular targets currently available to personalized medicine in thoracic oncology can be identified using this system in an appropriate TAT, notably when only a small amount of nucleic acids is available. We discuss the new challenges and the perspectives of using such an ultra-fast NGS in daily practice.

Clinical efficacy and safety of pemetrexed with or without either Bevacizumab or Pembrolizumab in patients with metastatic nonsquamous non-small cell carcinoma.

Pemetrexed was approved by United States Food and Drug Administration (US FDA) in combination with platinum for the treatment of advanced nonsquamous non-small cell lung carcinoma (NSCLC) and malignant mesothelioma. Bevacizumab and pembrolizumab can be added to chemotherapy for patients with nonsquamous NSCLC with benefits but there has not been any dedicated head-to-head comparison between pembrolizumab-pemetrexed-platinum (PAC) and bevacizumab-pemetrexed-platinum (BAC) on their efficacy and safety. This was a retrospective single-center cohort study conducted in Queen Mary Hospital in Hong Kong. The study included 451 patients with advanced stage nonsquamous NSCLC that received first-line pemetrexed and platinum with or without bevacizumab or pembrolizumab. Patients who received pemetrexed-platinum (AC) were compared with those who received PAC and BAC. The primary endpoint was the progression-free survival (PFS). The median PFS for patients that received PAC was significantly longer than those who received BAC and AC (9months vs. 6.8months vs. 4.8 months, p<0.05 among all three groups), with OR of 0.578 (95% CI, 0.343-0.976; p=0.040) and 0.430 (95% CI, 0.273-0.675; p<0.001) when compared to BAC and AC, respectively. Patients who received PAC also had a higher disease control rate and higher likelihood to receive continuation maintenance therapy than those on AC. There is no statistically significant difference in the grade 3 to 4 toxicity among the three treatment groups. Although both regimens are superior to pemetrexed-platinum alone, data fromthis retrospective single center study suggestedabetter PFS in advanced stage nonsquamous NSCLC patient treated with first-linepembrolizumab-pemetrexed-platinumthan bevacizumab-pemetrexed-platinum without an obvious increase in significant toxicity.

11P Results of a phase II study investigating eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab in second-line PD-1/PD-L1 refractory metastatic non-small cell lung carcinoma pts

Eftilagimod alpha (efti) is a soluble LAG-3 protein binding to a subset of MHC class II molecules to mediate antigen presenting cell (APC) and CD8 T-cell activation. Stimulating APCs and subsequent T cell recruitment with efti may revert PD-1 resistance. We hereby report results from part B, 2nd line PD-1/PD-L1 refractory non-small cell lung carcinoma (NSCLC), of the TACTI-002 trial. Patients (pts) with previously treated metastatic NSCLC, refractory to PD-1/PD-L1 and unselected for PD-L1 expression were enrolled. A Simon's 2-stage design was used, with objective response rate (ORR) by iRECIST as the primary endpoint (EP). Secondary EPs include ORR by RECIST 1.1, tolerability, disease control rate (DCR), progression free survival and overall survival. Pts received 30 mg efti (SC) q2w for 8 cycles (1 cycle= 3 wks) and then q3w for up to one year together with pembrolizumab (200 mg IV q3w for up to 2 years). Imaging was performed every 8 weeks and evaluated locally. The study was approved by relevant authorities and ethics committees. 36 pts were enrolled in this cohort. Median age was 66 years (50-84) and 61 % were male. The ECOG PS was 0 and 1 in 33 % and 67 % of pts, respectively. Pts had squamous (19 %) and non-squamous (78 %) NSCLC. Pts were pretreated with a PD-1/ PD-L1 antagonist alone (33 %) or in combination with platinum-based chemo (67 %). All PD-L1 subgroups were included with 36 % being PD-L1 negative. Pts received a median 4.0 (range 1–18) pembrolizumab and 5.0 (range 1-22) efti administrations. 2 pts discontinued treatment due to adverse reactions (ARs) (5.6 %). The most common (>15 %) AEs were decreased appetite (33 %), dyspnea (31 %), cough (25 %), asthenia (22 %), fatigue (17 %) and weight decreased (17 %). At data cut-off (Nov2021) 36 pts were evaluated for response with a min. follow-up of ≥4 months. ORR (iRECIST) and DCR was 6 % (2/36) and 36 % (13/36), respectively. Both responses were reported in pts pre-treated with chemo + PD-1 and under therapy since 7+ and 12+ months at data cut-off. Efti in combination with pembrolizumab is safe and shows encouraging signs of antitumor activity in PD-1 refractory 2nd line NSCLC pts.

Fusion-positive non-small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications.

Based on superior efficacy and tolerability, targeted therapy is currently preferred over chemotherapy and/or immunotherapy for actionable gene fusions that occur in late-stage non-small cell lung carcinoma (NSCLC). Consequently, current clinical practice guidelines mandate testing for ALK, ROS1, NTRK, and RET gene fusions in all patients with newly diagnosed advanced non-squamous NSCLC (NS-NSCLC). Gene fusions can be detected using different approaches, but today RNA next-generation sequencing (NGS) or combined DNA/RNA NGS is the method of choice. The discovery of other gene fusions (involving, eg, NRG1, NUT, FGFR1, FGFR2, MET, BRAF, EGFR, SMARC fusions) and their partners has increased progressively in recent years, leading to the development of new and promising therapies and mandating the development and implementation of comprehensive detection methods. The purpose of this review is to focus on recent data concerning the main gene fusions identified in NSCLC, followed by the discussion of major challenges in this domain.

Les mutations de KRAS dans les cancers pulmonaires non à petites cellules, opportunités thérapeutiques et nouveaux challenges pour le pathologiste

AbstractKRAS mutations are among the most frequent genomic alterations identified in non-squamous non-small cell lung carcinoma (NS-NSCLC), notably in lung adenocarcinoma. In most of the cases, these mutations are mutually exclusive of the different genomic alteration currently known to be sensitive to targeted therapies, notably present in EGFR, ALK, BRAF, ROS1 or NTRK. Recently, different promising clinical trials targeting KRAS G12C mutated NSCLC open new hopes for a better treatment of these tumors. In parallel, other studies have shown that NSCLC harboring co-mutations on KRAS, STK11 and KEAP1 demonstrated immunotherapy primary resistance. So, the assessment of KRAS status in late stage NS-NSCLC has become essential in order to set up an optimal therapeutic strategy in lung cancer patients. This has induced new algorithms for NSCLC sample management in the pathology laboratories and conditioned a new organization for the thoracic pathologists for an optimal health taking care of these patients.

Clinical Outcomes of Chemotherapeutic Molecules as Single and Multiple Agents in Advanced Non-Small-Cell Lung Carcinoma (NSCLC) Patients.

Background and Objectives: Lung cancer is the second most common cancer in the world. Non-small-cell lung carcinoma (NSCLC) makes up 85% of all lung cancer cases and the majority of patients are diagnosed when the cancer is advanced. Over the years, many anticancer drugs have been designed and introduced into the market to treat patients with advanced NSCLC. This review aims to discuss the comparative therapeutic benefits of conventional chemotherapeutics and other drugs available for treating advanced NSCLC. Materials and Methods: A literature search for first-line treatment of advanced NSCLC was carried out on PubMed and Google Scholar. Objective response rate (ORR) and overall survival were chosen as target endpoints. Results: Monotherapy showed lower treatment endpoints compared to combination therapy. Different combinations of platinum-based doublets demonstrated similar efficacies in treating NSCLC. However, pemetrexed–platinum doublets showed significantly better treatment endpoint in patients with non-squamous NSCLC. Most studies showing the best complete response rate (CRR) utilized epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), while most studies producing the best overall survival included programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors in their treatment regimens. Conclusions: The findings of this review indicate that targeted therapy using specific inhibitors is now the most promising first-line anticancer treatment available in the market. However, chemotherapy is still effective in treating advanced NSCLC and is viable as a first-line treatment.

Abstract 381: Elevated PARP7 expression in select cancers identifies a target population for RBN-2397 therapy

Abstract PARP7 (TIPARP) is a monoPARP which catalyzes the transfer of single units of ADP-ribose onto substrates to change their function. Its expression is upregulated during cellular stress, including viral infection or through the activation of the aryl hydrocarbon receptor after exposure to cigarette smoke. We and others have shown that PARP7 activity suppresses the Type I interferon (IFN) response following activation by cytosolic nucleic acid sensing pathways. RBN-2397 is a first-in class PARP7 inhibitor, which induces cancer cell autonomous and immune stimulatory effects in preclinical models through enhanced Type I IFN signaling in cancer cells. Here we describe the presence of PARP7 genomic amplification with corresponding increased mRNA expression across select cancers. Elevated PARP7 expression or amplification may identify cancer patients that could derive benefit from treatment with RBN-2397. In characterizing PARP7 copy number and mRNA expression from The Cancer Genome Atlas (TCGA) database, we found the presence of PARP7 copy number amplification in a subset of tumor types, particularly those of squamous histology, as well as ovarian cancer that corresponded to higher mRNA expression levels. High PARP7 expression correlated with poor survival in squamous cancers, while it had no effect on survival in ovarian cancer. Interestingly, tumor types with high PARP7 expression also expressed higher levels of baseline interferon stimulated genes (ISGs). This parallels our findings that cancer cell lines with higher ISGs at baseline are more responsive to PARP7 inhibition. To explore PARP7 copy number variations (CNVs) in advanced cancer patients, we queried the FoundationCore® (Foundation Medicine, Inc) database. Similar to TCGA, squamous cancers as well as ovarian, breast, and pancreatic ductal adenocarcinoma (PDAC) were among the tumor types with PARP7 amplifications. Moreover, PARP7 was found to be amplified both on the background of chromosome 3q arm-level amplifications as well as focally. Congruent to our analysis of PARP7 amplifications, we evaluated PARP7 mRNA expression in both squamous and non-squamous non-small cell lung carcinoma (NSCLC), breast cancer, and PDAC primary tumor samples. Using a validated RNAscope ISH probe set, we analyzed over 1,000 patient samples and found that PARP7 was more highly expressed in tumor cells relative to corresponding normal tissues. Overall, there were varying levels of PARP7 expression across samples with higher expression levels of PARP7 in tumor cells, compared to stroma, across all cancers examined. Our analyses describing the presence of PARP7 amplifications as well as high expression levels in several tumor types including NSCLC, breast, and PDAC provides evidence for the therapeutic relevance of PARP7 inhibition and highlights potential patient selection strategies to identify those patients more likely to benefit from RBN-2397 treatment. Citation Format: Jodie Wong, Kristy Kuplast-Barr, Ryan P. Abo, Anupriya S. Kulkarni, Linda T. Nieman, Azfar Neyaz, Katherine H. Xu, Radwa Sharaf, Lee A. Albacker, David T. Ting, Heike Keilhack, Kristen A. McEachern. Elevated PARP7 expression in select cancers identifies a target population for RBN-2397 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 381.

What Is New in Biomarker Testing at Diagnosis of Advanced Non-Squamous Non-Small Cell Lung Carcinoma? Implications for Cytology and Liquid Biopsy

The discovery and clinical validation of biomarkers predictive of the response of non-squamous non-small-cell lung carcinomas (NS-NSCLC) to therapeutic strategies continue to provide new data. The evaluation of novel treatments is based on molecular analyses aimed at determining their efficacy. These tests are increasing in number, but the tissue specimens are smaller and smaller and/or can have few tumor cells. Indeed, in addition to tissue samples, complementary cytological and/or blood samples can also give access to these biomarkers. To date, it is recommended and necessary to look for the status of five genomic molecular biomarkers (EGFR, ALK, ROS1, BRAFV600, NTRK) and of a protein biomarker (PD-L1). However, the short- and more or less long-term emergence of new targeted treatments of genomic alterations on RET and MET, but also on others’ genomic alteration, notably on KRAS, HER2, NRG1, SMARCA4, and NUT, have made cellular and blood samples essential for molecular testing. The aim of this review is to present the interest in using cytological and/or liquid biopsies as complementary biological material, or as an alternative to tissue specimens, for detection at diagnosis of new predictive biomarkers of NS-NSCLC.

Results from a phase II study of eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab in patients with PD-L1 unselected metastatic non-small cell lung carcinoma.

9046 Background: Eftilagimod alpha (efti) is a soluble LAG-3 protein that binds to a subset of MHC class II molecules to mediate antigen presenting cell (APC) activation and CD8 T-cell activation. The stimulation of the dendritic cell network and subsequent T cell recruitment with efti may lead to stronger anti-tumor responses in combination than observed with pembrolizumab alone. We hereby report results of the 1st line non-small cell lung carcinoma (NSCLC) part of the phase II trial (NCT03625323). Methods: Patients (pts) with untreated, immunotherapy naïve, advanced NSCLC unselected for PD-L1 expression were recruited into part A. The study used a Simon's 2-stage design (17 pts planned for stage 1 and 19 pts for stage 2), with objective response rate (ORR) by iRECIST as the primary endpoint (EP). Secondary EPs include tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS), PK, PD and immunogenicity. Efti is administered as 30 mg subcutaneous injection every 2 wks for 8 cycles and then every 3 wks for 9 cycles with pembrolizumab (200 mg intravenous infusion every 3 wks for up to 2 yrs). Imaging was performed every 8 weeks locally and with blinded independent central review (BICR) retrospectively. The study was approved by ethic committees and institutional review boards. Results: In total 36 pts were enrolled. At data cut-off (Jan 2021; median FU of 14 months), the median age was 69 yrs (range 53-84) and 69 % were male. The ECOG PS 0 and 1 was 42% and 58% respectively. Patients had squamous (42%) and non-squamous (58%) NSCLC and 95% presented with metastatic disease. All PD-L1 subgroups (TPS &lt; 1 %, ≥ 1 % to ≤49 %; ≥50 %) were represented with 36% pts having ≥50% TPS. Pts received a median of 7.0 (range 1 – 31) pembrolizumab and 11.5 (range 1-22) efti administrations. Responses as per BICR and local read are shown in the table. ORR (local, iRECIST) by different PD-L1 subgroups was 27% for pts with TPS&lt;1%, 39 % for TPS ≥1 %and 54% for ≥50 % TPS. Median PFS (n=36) was 8.2 months while median OS was not yet reached. The most common (&gt; 20 %) treatment emergent adverse events (AEs) were asthenia (47 %), cough (36 %), decreased appetite (36 %), dyspnea (32 %), pruritus (31 %), fatigue (28 %), diarrhea (25 %), anemia (25 %), constipation (25 %) and back pain (22%). Two patients discontinued treatment due to adverse reactions (Grade 4 immune-mediated hepatitis, Grade 3 AST+ALT increase). Conclusions: Efti in combination with pembrolizumab is safe and shows encouraging antitumor activity in 1st line advanced NSCLC patients across all PD-L1 (TPS) levels. Clinical trial information: NCT03625323. [Table: see text]