Non-small Cell Lung Cancer Pts Research Articles

A phase 2, open-label, single-arm study evaluating the combination of pembrolizumab (pembro), lenvatinib, and chemotherapy in patients (pts) with metastatic non-small cell lung cancer (NSCLC) harbouring a targetable mutation who experienced disease progression on standard tyrosine kinase inhibitors (TKIs).

198 Background: Pts with metastatic NSCLC harbouring a targetable mutation who progressed on standard TKIs often receive chemotherapy as the next line of treatment. We report efficacy and safety of a novel combination of pembro, lenvatinib and chemotherapy for these pts. Methods: This was a phase 2, open-label, single-centre, single-arm study enrolling pts with metastatic NSCLC with sensitizing EGFR, ALK or ROS1 mutation who progressed on standard TKIs. Eligible pts had measurable disease, no untreated brain metastasis and ECOG PS ≤1. Pts received pembro 200 mg, pemetrexed 500 mg/m2 and carboplatin AUC 5 every 3 weeks for 4 cycles plus lenvatinib 8 mg QD. The maintenance regimen without carboplatin was continued as tolerated for up to 2 years. The primary endpoint was objective response rate (ORR) by independent radiology review (IRR) as per RECIST 1.1. The secondary endpoints were PFS, overall survival (OS) and safety. Results: At the data cutoff date (2nd February 2024), 24 pts were screened and 19 were enrolled: median age 64 years (range 29–77); 10 (53%) female. Four pts were excluded at screening due to untreated brain metastasis. All enrolled pts were evaluated for safety while 15 pts were evaluable for response. All pts had adenocarcinoma with targetable mutation: EGFR mutation in 18 (95%) pts and ALK fusion in 1 (5%) pt. The median follow-up time was 11.3 months. Treatment was ongoing in 8 pts on the date of analysis, while 6 pts permanently discontinued due to disease progression and 1 pt permanently discontinued due to a treatment-related adverse event (TRAE). The ORR was 40% (6/15, 95% CI 19.8%–64.3%). All responses were partial responses. The median PFS was 11.9 months (range 3.5–20.3). The OS was not reached. TRAEs of any grade (Gr) occurred in 74% (14/19) of the pts. Most of the TRAEs were Gr 1–2, which occurred in 63% (12/19) of the pts. The most common TRAEs were hypothyroidism (31.6%), nausea (26.3%), neutropenia (26.3%), thrombocytopenia (26.3%), anorexia (21.1%), hypertension (15.8%), anaemia (10.5%), pruritus (10.5%) and rash (10.5%). G1 diarrhoea was reported in 1 pt (5.3%) and G1 adrenal insufficiency in 1 pt (5.3%). Gr 3 TRAEs were neutropenia in 2 pts, anaemia in 1 pt and thrombocytopenia in 1 pt. The only Gr 4 TRAE was thrombocytopenia. No treatment related death was observed. Conclusions: The combination of pembro, lenvatinib and chemotherapy demonstrated a favourable ORR and safety in treating metastatic NSCLC pts with a targetable mutation who progressed on standard TKIs. Clinical trial information: NCT04989322 .

Anti-ALK autoantibodies in patients with ALK-positive Non-Small Cell Lung Cancer (NSCLC): A monocentric experience

ImportanceDeregulation of anaplastic lymphoma kinase (ALK) occurs in 3–7% of advanced NSCLC mainly because of chromosomic rearrangements at the ALK locus. Next to its oncogenic function, ALK chimeric oncoprotein is a possible antigen for human immune system. The prognostic value of natural anti-ALK immunogenicity remains poorly explored in ALK ​+ ​NSCLC. We hereby report preliminary results of a plasmatic anti-ALK a-abs titration assessment in a cohort of ALK ​+ ​NSCLC pts. ObjectiveTo evaluate the prevalence of pre-existing circulating anti-ALK a-abs in ALK ​+ ​NSCLC pts. Key secondary objectives are the assessment of anti-ALK a-abs prognostic value and association with brain metastases (BM). DesignThis monocentric case series included 60 ALK ​+ ​NSCLC pts progressing on any anti-ALK TKIs between October 2015 and February 2021 ​at Gustave Roussy Cancer Campus. Fifty-six plasma samples were analyzed through a semiquantitative immunocytochemical technique. Plasma samples were obtained from two prospective studies approved by our Institutional Review Board: the MATCH-R trial (NCT02517892) and the MSN trial (RECF1256). ParticipantsWe included pts diagnosed with unresectable stage III or IV NSCLC, either by contemporaneous or historical biopsy. ALK-rearrangement was identified by FISH, IHC or NGS. Pts were aged more than 18-year-old and had previously signed informed consent for one of the studies. Pts had received at least one anti-ALK-TKI during the disease history. Pts were not eligible if they had been diagnosed with a second cancer. Main outcomes and measuresThe prevalence of plasmatic anti-ALK a-abs titer was reported as percentage. Progression-free survival, overall survival, and time to BM were analyzed using Kaplan-Meier methods. ResultsWe found an anti-ALK a-abs titer in 5 (9 ​%) pts. anti-ALK a-abs did not contribute to prolongation of survival. Although not significant, there was a trend towards protection against BM in the presence of anti-ALK a-abs. Conclusions and relevanceBecause ALK fusion proteins are exclusively produced intracellularly, not all ALK autoantibodies may have direct anti-tumor impact with favorable prognostic value. This is the first investigation to explore the impact of circulating anti-ALK a-abs on BM. Prospective studies with longer follow-up are warranted to further explore the impact of anti-ALK a-abs on BM.

Analysis of thromboembolic events in patients with non-small cell lung cancer treated with immune checkpoint inhibitors: A single-center real-world study.

e20580 Background: Thromboembolic events (TEEs) are serious complications leading to significant morbidities and mortality in cancer patients (pts). Although incidences of 7-17% for TEEs were reported in non-small cell lung cancer (NSCLC) pts undergoing palliative chemotherapy, there were few reports on TEEs in NSCLC pts receiving immune checkpoint inhibitor (ICI) monotherapy. Methods: This study retrospectively analyzed 232 pts with stage III/IV or recurrent NSCLC who initiated palliative ICI monotherapy (1st line: 52, ≥2nd line: 180) from September 2017 to August 2022 in a single center. TEE occurrences were confirmed in pts during ICI treatment or within 6 months post-completion, while TEEs after regimen change were excluded. Results: Pembrolizumab (107 pts) was the most frequently administered agent, followed by atezolizumab (63 pts) and nivolumab (62 pts). TEEs were identified in a total of 14 pts (6.0%), and pulmonary thromboembolism was the most common type of TEEs (7 pts). No significant risk factors associated with TEE occurrence were identified, including age, performance status, Khorana score, type of drugs, and the line of chemotherapy. Conclusions: TEEs occurred at a relatively lower incidence in NSCLC pts receiving ICI monotherapy compared to previous studies involving cytotoxic chemotherapy, particularly platinum-based regimens. Nevertheless, the incidence is non-negligible and careful monitoring for TEEs in NSCLC pts undergoing ICI monotherapy is needed.

Long-term survival of patients with lung cancer with kinase fusions (KF) treated at a tertiary community-based cancer program.

e23279 Background: Comprehensive Genomic Profiling (CGP) has been routinely obtained on patients with advanced cancers without standard-of-care therapeutic options managed in our community-based cancer program for more than a decade. Methods: In 2018, we reported that 1% (77 of 7,260 pts) who underwent CGP (Foundation Medicine Inc. hybrid capture based CGP platform) were found to have a KF abnormality (median age 53), including 55 patients (pts) (71%) with non-small cell lung cancer (NSCLC) and 22 (29%) with other malignancies. The incidence of KF in the NSCLC population tested was approximately 5%. Of the 55 patients with NSCLC, 36 pts (65%) had ALK fusions, 12 pts (22%) has RET fusions, 7 pts (13%) had ROS1 fusions. Results: This report describes long-term survival of NSCLC pts with metastatic disease within this population treated with KF targeted therapy for > 5 years. Five pts (9% of NSCLC with a KF; all females; median age 63 [range 57-72]) remain on active therapy a median of 10 years (range 6.5-12 years) from the initiation of therapy. 2 pts have EML4-ALK fusions, 1 pt has EZR-ROS1 fusion, 1 pt has CD74-ROS1 fusion, and 1 pt has ALK PRKAR1A fusion. 2 of 5 pts have continued their initial KF agent while 2 switched >1 times to an alternative KF targeted drug and 1 is currently receiving chemotherapy. Only two pts had the identical KF abnormality. Conclusions: In this series approximately 10% of NSCLC pts with a KF experienced extended survival (greater than five years) despite the presence of metastatic disease, including three patients with brain mets. It is critical to conduct molecular testing on all NSCLC pts for the presence of a kinase fusion abnormality. Treatment directed at this molecular target can result in long-term survival.

A real-world assessment of the treatment-related symptoms and associated burden among patients with lung cancer receiving chemotherapy.

e23159 Background: For patients (pts) with metastatic non-small cell lung cancer (NSCLC), treatment with chemotherapy has shown improved survival, symptom control, and increased quality of life. In clinical trials, the adverse event profile associated with these treatments has been identified. Less explored is the real-world experience of treatment-related symptoms and treatment burden. The objective of this study is to evaluate treatment-related symptoms and treatment burden among chemotherapy-treated NSCLC pts through an electronic remote symptom monitoring system. Methods: Pts diagnosed with NSCLC who received chemotherapy at U.S. academic cancer centers were enrolled in the Carevive’s Patient Reported Outcomes Mobile Platform (Carevive PROmpt®) from September 2020 - June 2023. 174 pts were enrolled. Weekly PRO-CTCAE-derived surveys assessed severity, frequency, and interference for 16 symptoms: anxiety, constipation, cough, decreased appetite, diarrhea, fatigue, general pain, insomnia, mouth/throat sores, muscle pain, nausea, numbness and tingling, rash, sadness, shortness of breath, and vomiting. The GP5 assessed weekly overall side effect treatment bother. Results: The mean age of NSCLC pts was 67.3 (SD = 9.2) years, with 51% female, and 12% African American. The majority of pts, 126 (72%), were enrolled at or within 1 month of the start of treatment. Ninety-one (52%) received chemotherapy and 83 (48%) received chemotherapy in combination. At enrollment, cough, fatigue, and shortness of breath was reported by > 40% of pts receiving chemotherapy, with constipation, decreased appetite, general pain, and numbness/tingling occurring in > 20% of pts. Over 40% of pts reported being at least “somewhat” bothered by the side effects of treatment. Pts with decreased appetite, nausea, and numbness/tingling were more likely to rate symptoms as “somewhat” or “very much” bothersome. No differences were noted for those with combination regimens. Conclusions: For real-world chemotherapy pts, the most frequent symptoms at enrollment were cough, fatigue, shortness of breath, decreased appetite, general pain, and numbness/tingling. Patients with decreased appetite and numbness/tingling were more likely to note higher treatment bother. Results show the feasibility of assessing symptom burden and corresponding patient bother in a real-world NSCLC population, which will have increasing importance increasing use of new treatment modalities with and without cytotoxic chemotherapy. [Table: see text]

Clinical activity and safety of naptumomab estafenatox (NAP) and docetaxel in patients (pts) with checkpoint inhibitor (CPI) –pretreated advanced/metastatic non-small cell lung cancer (NSCLC): Preliminary results of a P2 trial.

8615 Background: NAP is a chimeric protein composed of a superantigen (SAg) and a Fab targeting common tumor antigen 5T4, which is highly expressed in NSCLC. Its therapeutic effect is associated with activation, expansion, and tumor infiltration of SAg-binding specific T cells. Docetaxel is important therapeutic component in the treatment of advanced-stage NSCLC and SOC after failure of chemo-immunotherapy. We present initial results from this open label single arm trial, with advanced/metastatic NSCLC pts previously treated with at most 2 prior systemic therapies, including platinum-based chemotherapy and CPI, were treated with NAP and docetaxel. Methods: Patients were treated with NAP at 10 mcg/kg and docetaxel at a standard dose (75 mg/m2) in 21 day cycles for up to 2 years. If docetaxel was discontinued, NAP could be continued as monotherapy in 28 day cycles. Obinutuzumab pretreatment prior to cycle 1 used to inhibit anti-drug antibodies (ADAs) to NAP. Primary objective was overall response rate (ORR) and duration of response (DOR) based on institutional iRECIST review. Secondary objectives included safety, progression free survival (PFS) and overall survival (OS). Results: The trial enrolled 38 pts, 36 received NAP, 32 had post baseline imaging and were evaluable for response. Median age 66 yrs (33-85), 55% male, ECOG 0 in 26% and 1 in 74%. Eight pts (21%) had CNS involvement at baseline but brain MRI was not initially required, but implemented later in the trial. All pts received platinum-based chemotherapy and CPI, with a median of 2 (1-4) prior regimens. Nine pts (24%) received 2 CPI containing regimens. NAP safety was acceptable and consisted of mostly grade 1-2 infusion related reactions, were generally easily manageable and rapidly reversable that were in line with previous reports. Pts received median of 4 combination cycles and 14 pts (39%) continued NAP as monotherapy. NAP treatment was discontinued due to toxicities in 2 pts (5%). Five pts had PR, 2 of them unconfirmed, ORR 16%. Two pts had prolonged responses: one lasted for 22 m and the second had CR in target lesions lasted for 24 m with progression in brain treated with radiation, which did not compromise pts systemic response. One pt had initial pseudo-progression in target lesions with a subsequent PR, suggesting a possible immune response. Mean response duration was 7.3 m (1.3 - 20.8). Mean PFS was 4.6 m, 18 pts (56%) had SD, disease-control rate (DCR) was 72%, with mean duration of 5.3 m. Median OS was 8 months with 11 pts (34%) still alive at database lock and 3 pts receiving NAP under individual expanded access protocol. Conclusions: These preliminary results of NAP + docetaxel show potential evidence of activity with acceptable safety in heavily pre-treated NSCLC pts. Further trials of NAP in combination, including CPIs are planned. Clinical trial information: NCT04880863 .

Development and preliminary validation of a platform for systematic, unbiased pre-screening of non-small cell lung cancer (NSCLC) across three community oncology practices.

e23230 Background: With a rapidly increasing number of candidate drugs and clinical trials in oncology, efficiency in clinical trial execution has become a primary focus area for innovation. Currently, fewer than 5% of oncology patients enroll in clinical trials, and data suggests a lack of diversity in clinical trial patient populations compared to the broader patient demographic. To address these issues, we developed a systematic unbiased pre-screening platform for all patients. This approach holds the promise of hastening clinical trials by enhancing the identification of eligible patients and concurrently promoting diversity among those invited to participate in these trials. Methods: A framework for use of EMR ingested data and standardized abstraction of select 160 variables was developed for patients with NSCLC. An algorithm based on 7 key eligibility criteria was developed to generate an automated assessment of eligibility for a presumed trial. Abstracted data was compared to a medical oncologist’s assessment (gold standard) and the automated tool was validated by comparing eligibility assessment before each visit with that of a medical oncologist. Results: Three community oncology practices in the US participated. Source data-verified values for histology, ECOG PS, treatment history, line of therapy, and current metastatic status were available for > 90% of patients in real-time. Tumor NGS testing rates for actionable alterations exceeded 75%. From Oct 23, 2023 to Jan 14, 2024, 786 NSCLC pts had MD visits. Preliminary validation of the automated tool in 79 patients revealed concordant classification in 76/79 pts (96.2%). Sensitivity, specificity, PPV and NPV were > 90%. Concordance for all variables was 98% between the abstractor and medical oncologist. Conclusions: A platform for systematic, unbiased pre-screening of patients for clinical trials in NSCLC has been developed to support and facilitate oncology sites without imposing financial or resource burdens or affecting routine clinical workflow. Preliminary validation supports high performance. Updated validation data will be presented in the meeting. The high levels of data completeness and quality, including NGS testing rates that are substantially higher than what has previously been reported in community centers, underscore their suitability as clinical trial sites.

Association of lung cancer-associated cachexia with the metastatic spread to pleura.

12095 Background: Cancer-associated cachexia (CAC), a major contributor to mortality in patients with non-small cell lung cancer (NSCLC), is characterized by alterations in body composition. Here, we explore the associations between body composition changes and the pattern of lung cancer metastatic spread. Methods: Computer tomography (CT) images from cancer diagnosis and recurrence were used to quantify subcutaneous and visceral adipose tissue (SAT, VAT) and skeletal muscle (SKM) tissue areas at the 3rd lumbar vertebrae level, using an DAFS AI-based software, Voronoi Analytics, in 101 NSCLC pts, who relapsed after surgical treatment of the primary tumor at the Medical University of Gdansk Hospital. The decrease in SKM, SAT and VAT of more than 5% or 10% at cancer relapse was compared with the pattern of cancer recurrence. Results: The median time to recurrence after primary tumor resection was 1.6 years (0.4–6.4 years). There were 38% local or regional recurrences, 59% distant recurrences, and 13% second primary lung cancers. Among the cases with distant recurrence, there were 19% brain recurrences, 22% pleural metastases, 34% lung metastases, 17% bone metastases, and 11% cases of liver relapse. More than one site of distant recurrence occurred in 51 (50%) of patients. Loss of > 5% of SKM, SAT and VAT occurred in 61%, 33% and 41% respectively. Loss of >5% or >10% of SKM was associated with the pleural metastases at the time of cancer recurrence, ( P < 0.001). Median muscle loss was –11.6% for patients with pleural relapse and –5.3 % for patients with other metastatic locations ( P < 0.001). There were no significant associations between other body composition changes and the pattern of recurrences, tumor histology or age. Conclusions: NSCLC relapse to the pleura after surgical treatment of the primary tumor, appears to be associated with a decrease in the skeletal muscle compartment. This finding may inform the design of the future studies aiming to investigate molecular correlates of sarcopenia and cancer-associated cachexia.

Phase I summary of the HB0025 efficacy and safety to the heavily pretreated non-small cell lung cancer (NSCLC) population.

e14600 Background: HB0025 is a recombinant humanized bispecific molecule built on IgG1 that targets the human programmed death ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF, VEGF-A, VEGF165). Here we present the NSCLC results in Phase 1 study. Methods: This ongoing, open-label, multicenter, dose escalation and dose expansion, phase 1 trial to evaluate the safety and efficacy of HB0025 for pts with advanced solid tumors. HB0025 is administered intravenously every 14 days (Q2W). Response was evaluated by RECIST v.1.1 every 8 weeks. Results: As of Dec 25, 2023, 12 (7M/5F) NSCLC pts have received HB0025 at doses of 3mg/kg (n=1), 6mg/kg (n=2), 10mg/kg (n=2), 12mg/kg (n=1), 20mg/kg (n=5), 30mg/kg (n=1). Overall, the median age was 61.5 years, the median number of prior treatment lines was 4. The histologic types include squamous cell (Sq)-NSCLC (2 pts) without EGFR/ALK mutation and non- squamous cell (Nonsq)-NSCLC (10 pts), among of Nonsq-NSCLC 9 pts carrying EGFR/ALK mutation. The 3 pts with EGFR/ALK wild-type gene fail to prior anti-PD-1 treatment, 9 pts with EGFR/ALK gene mutation fail to prior TKI therapy. Among the 12 pts having imaging tumor assessment, the ORR was 25% and DCR was 66.7%, which included 3 partial responses (PR) ,5 stable disease (SD), and 4 progressive disease (PD) according to RECIST v1.1.For the 2 Sq-NSCLC pts, one pt achieved PR with 3mg/kg HB0025 treatment, the other pt achieved SD. For the10 Nonsq-NSCLC pts, there were 2 PR (20mg/kg and 30mg/kg treatment, respectively), 4 SD and 4 PD. Till the report date, the PR status and HB0025 treatment are ongoing to 3 PR pts, which includes 1 Sq-NSCLC pt, and 2 Nonsq-NSCLC pts which one pt doesn’t carry EGFR/ALK mutation. The Sq-NSCLC pt whose maximum tumor regression is 60% achieves PR after 4 cycles of treatment, and the duration of response (DOR) is more than 22 months. The one Nonsq-NSCLC pt whose maximum tumor regression is 74% achieves PR after 2 cycles of treatment, and the DOR is more than 11 months. The other Nonsq-NSCLC pt whose tumor regression is 32% achieves PR after 4 cycles of treatment, and the DOR is more than 2 months. Among the 5 SD pts, 1 Sq-NSCLC pt’s progression-free survival (PFS) is more than 14 months and continusous, 2 Nonsq-NSCLC pts’ PFS is more than 6 months and ongoing. For the 12 pts, 11 pts (91.7%) experienced a treatment related adverse events (TRAEs). The most common TRAEs included proteinuria (50%, 6/12), lymphocyte count decrease (50%, 6/12), blood bilirubin increased (33.3%, 4/12), and blood pressure increased (33.3%, 4/12). TRAEs ≥ grade 3 occurred in 2 (16.7%) pts. No TRAE leading to discontinuation and death. Conclusions: HB0025 monotherapy showed an acceptable safety profile and promising anti-tumor activity for prior heavily treated NSCLC, no matter in TKI-resistant population with EGFR/ALK mutation or population failed to anti-PD-1 treatment. Now Phase II studies of combination chemotherapy are ongoing. Clinical trial information: NCT04678908 .

Overall survival after treatment with CAN-2409 plus valacyclovir in combination with continued ICI in patients with stage III/IV NSCLC with an inadequate response to ICI.

8634 Background: Patients with unresectable non-small cell lung cancer (NSCLC) with an inadequate response to immune checkpoint inhibitors (ICI) have limited therapeutic options and expected median overall survival (mOS) of 11.6 to 14.5m (PMID: 35658002 ). The immunosuppressive tumor microenvironment and the lack of a specific T cell response underpin inadequate clinical response. CAN-2409 is a replication-defective adenovirus encoding the HSV-tk gene. Transduced cells activate orally delivered valacyclovir, resulting in immunogenic cell death, and in situ immunization against the patient’s tumor antigens, eliciting a specific immune response against the injected tumor and uninjected metastases. Methods: NCT04495153 is an open-label, phase 2 clinical trial of CAN-2409 + valacyclovir in combination with continued ICI in patients with non-resectable, stage III/IV NSCLC, refractory or resistant to anti-PD-(L)1. Patients were enrolled in 2 cohorts (C) depending on disease status at enrolment: C1, stable disease or C2, progressive disease. Two doses of CAN-2409 (5x1011vp) were given 5-7w apart via bronchoscopic or percutaneous injection into lung tumor, disease-positive lymph node, or peripheral metastasis, each followed by oral prodrug. Patients were assessed for safety, immunologic biomarkers, and OS. Results: As of 16Jan2024, 73 patients were treated (safety population: ≥1 dose of CAN-2409) and 44 were evaluable per protocol (received 2 doses of CAN-2409+ valacyclovir and 12-week CT scan). Baseline treated pt median age was 67 [43-88] yrs, 44% female, 68% on aPD(L)1 alone and 32% aPD(L)1 + pemetrexed regimen. We observed no dose-limiting toxicities or ≥grade 4 treatment-related AEs. mOS of the evaluable population was estimated as 22.0m (95% CI: 14.3m, NA; median follow up (mFU) time of 18.2m). In C2 (n = 38) mOS was 20.6 (mFU 19.2.m) and in C1 (n = 6) was N.A. (mFU 15.2m). mOS in the safety population (n = 73) was 14.3.m (mFU16.8m). 64% of evaluable patients had systemic clinical response with shrinkage of both injected and uninjected lesions. We found a significant correlation between increases in T cell populations after the second injection of CAN-2409 (circulating memory and effector memory CD4+ and CD8+T cells, CD4+ Ki67+IFNg+ and CD4+granzymeB+ T cells, CD8+granzymeB+Ki67+ T cells, T regulatory cells) and subsequent OS (R2 between 0.181 and 0.354 and p = 0.043 and 0.004). Conclusions: Experimental treatment with CAN-2409+valacyclovir in NSCLC pts following an inadequate response to ICI is well tolerated and results in the induction of a cytotoxic and memory circulating T cell response associated with shrinkage of injected and uninjected lesions and a raised tail of the survival curve. mOS of the evaluable population was estimated as 22.0m, markedly longer than the expected mOS of 11.6-14.5m. Clinical trial information: NCT04495153 .

Association of combination tumor texture and vessel tortuosity with progression free survival across PD-L1 subgroups in durvalumab treated non-small cell lung cancer (NSCLC): Blinded validation results from CP1108.

8600 Background: Immunotherapy (IO) has shown a durable response with minimal toxicity in the treatment of metastatic NSCLC. However, only 30-50% of these patients (pts) actually respond. Despite initial optimism surrounding PD-L1 expression as a potential biomarker, IO provides benefit across PD-L1 low (<25%) and high (≥25%) status. This highlights a critical need for more effective biomarkers to guide treatment decisions. Here, we present blinded validation results of a CT-based biomarker of change in quantitative vessel tortuosity (1) (Δ-QVT) and texture radiomics (2) (Δ-Rad) between baseline (B) and 6 weeks post-treatment (TP1) for predicting response, overall survival (OS) and progression free survival (PFS) in CP1108 (NCT01693562). Methods: CT scans at B and TP1 were retrospectively analyzed from two studies (a) a multi-center training set (Str, N=110) of metastatic NSCLC pts treated with first line IO and (b) a blinded NSCLC cohort of N = 151 pts treated with Durvalumab in CP1108 study (Sv). In Sv, N=75 pts were PD-L1 high (Sv+) whereas N=65 pts were PD-L1 low (Sv-). An in-house MATLAB based algorithm was used to extract intra-tumoral, peri-tumoral texture and QVT features from up to two largest measurable tumors in each CT. A classifier (MCombo) was trained on Str to predict best overall response defined as per the RECIST v1.1 criteria using combination of Δ-QVT and Δ-Rad features. Area under the receiver operating characteristic (AUC) was used to evaluate MCombo against RECIST response whereas univariable and multivariable Cox regression models with log-rank test, hazard ratio (HR) with confidence interval (CI) and concordance index (C-index) were used to study the association of MCombo with OS and PFS in Sv, Sv+, and Sv-. Results: MCombo predicted objective response with an AUC of 0.78 in Sv and was statistically significantly associated with PFS (Table) in Sv, Sv+, and Sv-. MCombo was associated with OS in Sv, Sv+, but not in Sv-. Multivariable analysis with PD-L1 status, histological subtype, ECOG status, liver metastasis, line of therapy and sex showed independent association of MCombo across OS and PFS. Conclusions: Our results indicate that combination of radiomics and vessel tortuosity biomarker from CT is independently prognostic of response and PFS across PD-L1 levels. Prospective validation of this biomarker is needed. 1. Alilou et al. Sci Adv 2022. 2. Khorrami et al. Cancer Immunol Res 2020. [Table: see text]

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 .

Overall survival (OS) in a u.s. Asian population with stage IV NSCLC with EGFR mutations treated with first-line (1L) osimertinib (Osi) compared to earlier generation (Gen) of TKIs or sequential treatment (Tx).

e20597 Background: Osi, a 3rd-gen EGFR tyrosine kinase inhibitor (TKI), was approved as 1L tx for metastatic non-small-cell lung cancer (NSCLC) with EGFR mutations (ex19del or L858R) in 2018. This was based on the FLAURA trial, showing improved progression-free survival and OS of 1L osi compared to 1st-gen TKIs. Despite this, subgroup analyses revealed no OS difference in Asian or L858R patients (pts). Studies such as GioTag and UpSwinG showed better median OS in Asians with ex19del mutations on sequential afatinib and osi tx, prompting the question if sequencing of tx may also benefit L858R pts. We conducted this analysis of real-world outcomes in U.S. Asian pts with EGFR mutated NSCLC treated with 1L osi, 1st- or 2nd- gen TKIs (prior-TKIs-only), or sequential 1st- or 2nd- gen TKI followed by osi (sequential-TKI-osi). Methods: We conducted a single-institution IRB-approved retrospective study at NYU, including Asian pts diagnosed with stage IV NSCLC with EGFR ex19del or L858R, who received any gen of TKIs from 1/1/2010 to 1/13/2023. We compared 3-year (3y) OS based on tx and mutation subtypes, excluding pts with less than 3 years of follow-up. The analysis utilized the Cox proportional-hazards model to calculate hazard ratios (HR) and P values of OS. Survival curves were estimated using the Kaplan-Meier method. The log-rank tests were used to assess survival differences between tx groups. Additionally, a multivariable Cox proportional-hazards model explored the association between pts' survival time and multiple predictor variables. Results: We analyzed 139 cases: 103 (74%) females, 68 (49%) L858R, 113 (81%) never smokers, and age 31-96 years. The 3y OS analysis revealed no significant difference in the OS in L858R pts who received prior-TKIs-only (p = 0.83) or sequential-TKI-osi (p = 0.90), compared to 1L osi (median OS not reached in all three groups). However, in ex19del pts, prior-TKIs-only (HR 0.31, 95% CI 0.13-0.76) and sequential-TKI-osi (HR 0.30, 95% CI 0.11-0.85) txs showed superior OS compared to 1L osi, with a median OS of 24.7 mo in 1L osi and not reached in other two txs. Among all predictor variables (tx, age, sex, EGFR subtypes, and smoking status), only age had a significant but small impact on OS (HR 1.03, 95% CI 1.01-1.06). Conclusions: Our real-world analysis revealed that Asian stage IV NSCLC pts with L858R treated with 1L osi had a similar 3y OS compared to those treated with prior-TKIs-only and sequential-TKI-osi. Whereas, 1L osi was inferior to both txs in OS for ex19del pts. This finding may be unique and significant in Asian ex19del pts, though our analysis is limited by the small cohort of a retrospective study. Larger cohorts from retrospective studies or prospective trials are needed to investigate the response of Asian ex19del pts to 1L osi, while underling the need for novel tx options for L858R pts.

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.

Abstract 2490: Quantification of tumor fraction and outcomes association in a real-world non-small cell lung cancer (NSCLC) cohort using a tissue agnostic epigenomic circulating tumor DNA (ctDNA) assay

Abstract Background: The validity of ctDNA assays for evaluating molecular response to therapy by measuring changes in variant allele fraction (VAF) while on treatment is well established, but they are prone to limitations such as low ctDNA levels and interference from copy number variation and clonal hematopoeisis (CH), which may be overcome by methylation-based quantification. ctDNA levels may be monitored throughout a patient's (pts) journey to indicate when relapse or progression is present, often sooner than current methods (RECIST). Here we describe the performance of a methylation-based ctDNA assay to quantify ctDNA levels and correlate changes with outcomes in a real-world NSCLC cohort. Methods: RADIOHEAD is a pan-tumor observational study of 1200 patients on standard of care ICI treatment regimens with plasma samples collected prospectively for retrospective analysis. We randomly selected 241 NSCLC pts that have a combined total of 761 samples (236 baseline, 191 C3D1, and 128 at 6 months post first dose). Samples were analyzed using a commercial NGS assay, which quantifies circulating tumor fraction (cTF) via interrogating thousands of methylation sites from ctDNA, validated with LoB, LoD, LoQ, and linearity studies. Cox proportional hazards (CPH) were used for comparison of real-world progression free survival (rwPFS). Gender, age, disease stage, and blood-assessed tumor mutational burden (bTMB) were included as covariates. Median rwPFS was calculated using Kaplan Meier analysis. rwPFS ordinal groups were defined as PFS event within 3mo, 3-6mo, 6-12mo, and greater than 12mo, and association with early ctDNA changes was assessed with a chi-squared test. Results: In this cohort, 4, 11, 83 and 142 pts were stage I to IV, respectively (1 unknown). Methylation based detection of ctDNA at baseline or C3D1 was associated with shorter rwPFS (baseline: mPFS 12.7 mo [9.3-19.5] vs NR [16.4-NR]; HR=2.2 [1.3-3.7] p<0.005, C3D1: mPFS 12.4 mo [9.3-16.1] vs NR [19.5-NR] HR= 2.2 [1.3-3.5], p<0.005) independent of stage, gender, or age. Longer rwPFS was associated with >95% reduction in cTF from baseline to C3D1 or low ctDNA at both timepoints (rwPFS <3mo = 12.5%, 3-6 mo = 30.8%, 6-12 = 37.1%, ≥12 mo = 55.3%; N=153, p=0.015). For pts with ctDNA not detected at C3D1, ctDNA detection at 6 months post first dose was strongly associated with shorter rwPFS (mPFS 13.5 mo [9.5-NR] vs. NR [19.5-NR]; HR= 6.2 [1.9-20.1], p<0.005). Conclusions: These data demonstrate a significant association of ctDNA detection via methylation-based cTF and on-treatment changes in cTF with rwPFS. Furthermore, subsequent cTF detection 6-months on-treatment, without cTF detected early on-treatment was associated with worse outcomes, suggesting the value of serial monitoring to improve identification of patients likely to progress. Citation Format: Sara Wienke, Sean Gordon, Samantha Liang, Jing Wang, Reagan Barnett, Kyle Chang, Shile Zhang, Carin R. Espenschied, Katie Quinn, Kimberly Banks. Quantification of tumor fraction and outcomes association in a real-world non-small cell lung cancer (NSCLC) cohort using a tissue agnostic epigenomic circulating tumor DNA (ctDNA) assay [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 2490.

Comparison of molecular testing rates and biomarker positivity by histology among patients (pts) with stage IV non-small cell lung cancer (NSCLC): A quality initiative by Integra Connect PrecisionQ.

582 Background: National Comprehensive Cancer Network guidelines for NSCLC recommend biomarker testing for EGFR, ALK, ROS1, BRAF, NTRK1/2/3, METex14 skipping, KRAS, RET, and ERBB2 (HER2) in advanced or metastatic NSCLC regardless of histology. We sought to understand the testing rates for these markers among pts with a squamous (S) histology compared to pts with a non-squamous (NS) histology, while also assessing positivity rates among pts based on histology by the respective biomarkers for pts with stage IV NSCLC. Methods: We used the Integra Connect PrecisionQ real-world de-identified database of over 2 million cancer pts across 500 sites of care to assess testing rates and biomarker positivity rates based on histology among adult NSCLC patients. We included 3,889 Stage IV NSCLC pts, where we conducted chart reviews, investigating testing rates across each of the biomarkers based on patient histology (group 1). In addition, we evaluated 6,303 stage IV NSCLC pts, regardless of whether we conducted chart reviews, to assess rates of positivity among the respective biomarkers (group 2). Pts included in the analysis were diagnosed on or after 1/1/2019. We assessed rates of biomarker testing in group 1 and biomarker positivity (irrespective of the type of mutation) in group 2 stratified by histology. Descriptive analyses were used and proportions were compared using a two-tailed two-sample z-test. Results: Among the Group 1 stage IV pts in the comparison of tested vs. not-testedbased on histology (N= 3889), the average age was 72.9 (median = 75), 49% were female, 81.6% were NS. We found the testing rates among S pts (N=714) vs. NS (N=3175) as follows: EGFR-S 76% vs. EGFR-NS 92%, ALK-S 77% vs. ALK-NS 92%, BRAF-S 75% vs. BRAF-NS 87%, KRAS-S 71% vs. KRAS-NS 81%, MET-S 72% vs. MET-NS 80%, RET-S 72% vs. RET-NS 79%, ROS1-S 72% vs. ROS1-NS 79%, ERBB2-S 69% vs. ERBB2-NS 76%, and NTRK-S 62% vs. NTRK-NS 68%. All comparisons were statistically significant at P < .01. Among the Group 2 stage IV pts who were tested(N = 6303), the average age was 72.6 (median = 73), 50.8% were female, 86.0% were NS. We found the positivity rates among S pts vs. NS pts as follows: EGFR-S 7.5% (N = 827) vs. EGFR-NS 19.5% (N = 4650), ALK -S 1.3% (N =837) vs. ALK-NS 3.6% (N = 5099), BRAF-S 2.8% (N = 742) vs. BRAF-NS 6.0% (N = 4399), KRAS-S 10.4% (N = 694) vs. KRAS-NS 31.1% (N=3763), MET-S 4.3 (N=645) vs. MET-NS 7.5% (N = 3537), RET-S 0.5% (N = 635) vs. RET-NS 1.4% (N= 3397), ROS1-S 0.6% (N = 629) vs. ROS1-NS 1.4% (N = 3346), ERBB2-S 2.2% (N = 504) vs. ERBB2-NS 3.8% (N = 2510), and NTRK-S 1.0% (N = 486) vs. NTRK-NS 1.5% (N = 2444). Conclusions: Our results indicate a need to increase biomarker testing among pts with S histology to be equivalent to those who were tested with a NS histology, as biomarker positivity rates present in pts with S histology warrant a molecular evaluation regardless of histology.

Sintilimab, SBRT and GM-CSF for Metastatic NSCLC: A Prospective, Multicenter, Phase II Trial

PD-1/PD-L1 inhibitors have transformed the therapeutic landscape in metastatic non-small cell lung cancer (NSCLC). However, the objective response rate (ORR) remains limited in unselected population. Incorporating SBRT to PD-1/PD-L1 inhibitors may improve treatment efficacy and the anti-tumor immunity induced by SBRT may be enhanced by GM-CSF, which plays a pivotal role in dendritic cell differentiation and maturation. The current trial (NCT04106180) is the first prospective, multicenter, phase II study assessing the safety and efficacy of a PD-1 inhibitor (Sintilimab), SBRT and GM-CSF in metastatic NSCLC patients without sensitizing driver mutations. Metastatic EGFR/ALK negative NSCLC pts who had failed first-line standard chemotherapy were eligible. Pts received SBRT (8 Gy*3) to one lesion, followed by Sintilimab (200 mg d1, every 3 weeks) and GM-CSF (125 μg/m2 d1-d14, cycle 1) within 3 weeks after SBRT. Sintilimab would be given continuously until disease progression, unacceptable toxicity, or up to 35 cycles. Primary end point is ORR. Secondary end points are safety, out-of-field response rate, overall survival (OS), progression free survival (PFS). The trial was designed to enroll 56 patients and if ≥17 pts evaluated had an objective response, it was regarded as positive. By the time of 2022/10/30, the trial was early closed after 18 of the 51pts enrolled from 6 academic centers documented PR. The majority of pts were male, ECOG 1 and non-squamous NSCLC, having more than 5 lesions at baseline, with a median age of 62 (range, 32-74). The sites of SBRT included lung (n = 20), regional lymph node (n = 16), pleural nodule (n = 5), vertebra (n = 3), distant lymph node (n = 3), liver (n = 2) and others (n = 2). Treatment-related adverse event (TRAE) occurred in most pts and grade 3 TRAE occurred in 6 (11.8%) pts. No grade 4-5 TRAE occurred and the most common grade 3 TRAEs were ALT/AST elevation (n = 2), transient acute heart failure (recovered within 7 days) (n = 1), leucopenia/neutropenia (n = 2), pneumonitis (n = 1) and creatinine elevation (n = 1). With a median follow-up of 19.2 (range, 4.6-35.4) months, 49 pts had evaluable efficacy, with 18 PR, 15 SD and 16 PD. Median PFS and OS were 5.9 (95% CI, 3.9-9.2) and 16.2 (95% CI, 12.6-34.1) months, respectively. The results of biomarker testing will also be presented. Triple combination of Sintilimab, SBRT and GM-CSF is safe and shows promising efficacy in metastatic EGFR/ALK negative NSCLC.

Friendly-user score assessing gut dysbiosis and resistance to immune checkpoint inhibitors (ICI).

103 Background: Accumulating evidence pointed to the impact of the intestinal microbiota on ICI outcomes across various cancers. Although specific gut microbial species have been associated with beneficial responses ( i.e. Akkermansia muciniphila (Akk)), no consensus exists on a gut fingerprint predicting immunoresistance to clinical routine use. Methods: NCT04567446 provided whole genome sequencing (WGS) of longitudinal fecal samples from patients (pts) with advanced non-small cell lung cancer (NSCLC) during ICI (alone or with chemotherapy) in France and Canada. Topological Pearson networks clustered into species interacting groups (SIG) correlating with overall survival (OS; OS<12=NR; OS>12=R). Forty harmful (SIG1) and thirty-four beneficial (SIG2) WGS species were associated with NR and R to ICI. A monodimensional score (TOPOSCORE) based on SIG1/SIG2 ratio combined with Akk relative abundance was calculated and compared to machine-learning (ML) algorithms. Multivariate Cox analysis (MVA) adjusted for established risk factors (ATB, gender, age, ECOG, PD-L1, LIPI score). Intraindividual dynamics of the TOPOSCORE was evaluated in pts with at least two fecal samples. Three independent cohorts of NSCLC and genitourinary (GU) cancers pts validated the data. Results: In n=245 and n=148 NSCLC pts, we could classify pts into dysbiotic (SIG1+,33%) and eubiotic (SIG2+, 67%), using the TOPOSCORE. Pts falling within the SIG2+ exhibited a significantly prolonged OS than pts falling into SIG1+ (HR: (95% CI), 0.50 (0.36-0.71), p<0.0001). TOPOSCORE also predicted OS in 277 ICI-treated NSCLC and GU pts and compared to the state-of-the-art ML algorithms, held the highest percentage of correct predictions (63%). At MVA, TOPOSCORE was independently associated with OS (HR: 0.56 (0.39-0.81), p=0.002). Analyzing the intraindividual dynamics of the TOPOSCORE (n=67), we found that 74% of SIG2+ and 68% of SIG1+ individuals remained in their initial classification during ICI treatment. We finally scaled the calculation of the TOPOSCORE down to 24WGS (instead 75WGS) and set up a qPCR-based friendly-user test capable of accurately identifying the fecal presence of the bacteria of interest within 48 hrs. We confirmed (n=323) that OS was superior in those pts harboring a 24-bacteria-qPCR-based TOPOSCORE falling within the SIG2+ category (HR: 0.65 (0.48 to 0.87), p=0.0005). Conclusions: TOPOSCORE represents a robust biomarker predicting and following the dynamic of the immunoresistance to ICI across cancers on an individual basis. By converting the WGS TOPOSCORE to a qPCR-based test with a rapid turnaround time, it will be possible to adopt this score in routine clinical practice to improve pts stratification and ICI success rates guiding the selection of dysbiotic pts amenable to microbiota-centered interventions and eubiotic fecal microbiota transplantation donors. Clinical trial information: NCT04567446 .

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]