Platinum Doublet Research Articles

VP5-2023: Primary results from BEATcc (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030), a randomised phase III trial of first-line atezolizumab (atezo) combined with a platinum doublet and bevacizumab (bev) for metastatic (stage IVB), persistent or recurrent cervical cancer (R/M CC)

VP5-2023: Primary results from BEATcc (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030), a randomised phase III trial of first-line atezolizumab (atezo) combined with a platinum doublet and bevacizumab (bev) for metastatic (stage IVB), persistent or recurrent cervical cancer (R/M CC)

How quickly are novel cancer therapies adopted after FDA approval and incorporation into EHR-embedded clinical decision support tools? A description of ordering patterns between users and non-users of an EHR-embedded oncology CDS tool.

508 Background: Oncology clinical decision support (CDS) tools provide up-to-date access to changes in treatment guidelines and notification of newly approved therapies to keep providers informed of rapid changes in the oncology environment. Our goal is to describe ordering patterns of oncologists who use an EHR-embedded CDS tool and those who do not after FDA approval for a new regimen combination and subsequent availability in the CDS tool. Methods: Flatiron Assist is a customizable CDS tool embedded in the electronic health record (EHR) to facilitate selection and documentation of National Comprehensive Cancer Network (NCCN) guideline concordant cancer care. This tool is updated on a monthly basis whereby updates to the NCCN guidelines are incorporated with subsequent communication delivered to users. For this retrospective description, we compared time in days to the first regimen order placed at 13 community oncology practices (348 MDs) using the CDS tool to 30 community oncology practices (294 MDs) not using the CDS tool. We focused on regimens ordered for the combination of nivolumab + platinum doublet (FDA approved on 3/4/22, incorporated into the NCCN guidelines on 3/16/22 and released in the CDS tool on 4/12/22) for neoadjuvant therapy in non-small cell lung cancer (NSCLC). Time to first order placed in practices that did and did not use the CDS tool was described as mean days with 95% confidence intervals (CI) and compared using linear regression with adjustment for number of MDs within a practice and robust standard errors from 4/12/2022 to 5/19/2023 which included 211 unique orders. Results: Of the 211 orders assessed during the observation window, the mean time to first order was 150 days (95% CI 118-182) for CDS tool users and 209 days (95% CI 177-242) for non-CDS tool users, favoring CDS tool users by 59 days (P=0.009, Table 1). Conclusions: Users of an EHR-embedded CDS tool ordered a new regimen sooner after FDA approval than non-users of the CDS tool. Limitations include the narrow sample size and evaluation of only one FDA approval. Future research will investigate whether the same benefit is seen for label expansions compared to net new regimen approvals as well as the impacts on outcomes and indicators of improved quality of care.[Table: see text]

EP13.03-09 Outcomes of ES-SCLC Patients Treated with Platinum Doublet and Immunotherapy: A Western Australia Retrospective Review

EP13.03-09 Outcomes of ES-SCLC Patients Treated with Platinum Doublet and Immunotherapy: A Western Australia Retrospective Review

EP12.01-11 Efficacy of Amivantamab in a Patient with EGFR ex20ins Lung Adenocarcinoma with Symptomatic Pleural Effusion after Platinum Doublet Failure

EP12.01-11 Efficacy of Amivantamab in a Patient with EGFR ex20ins Lung Adenocarcinoma with Symptomatic Pleural Effusion after Platinum Doublet Failure

Atezolizumab addition to platinum doublet: evaluating survival outcomes for patients with extensive disease small cell lung cancer.

The efficacy of adding atezolizumab to the platinum doublet regimen for extensive disease small cell lung cancer (ED-SCLC) remains marginally limited. We retrospectively assessed the real-world efficacy and safety of atezolizumab in addition to carboplatin and etoposide (EP + A), versus carboplatin and etoposide (EP) alone in previously untreated ED-SCLC patients. From a total of 99 patients, 46 were assigned to the EP + A group, and 53 to the EP group. No significant difference was observed in progression-free survival between the groups. However, the overall survival (OS) was significantly longer in the EP + A group (20.8 vs 12.1months; HR: 0.52; p = 0.0127). Patients older than 70years, male, with performance status 0-1, without liver metastasis, and low levels of C-reactive protein and neutrophil-lymphocyte ratio, experienced longer OS in the EP + A group compared to the EP group. The addition of atezolizumab to the platinum doublet regimen significantly extended OS in ED-SCLC patients, particularly among certain subgroups, suggesting its potential value in personalized treatment strategies. Further investigation is warranted to validate these findings.

Prior treatment with oxaliplatin-containing regimens and higher total bilirubin levels are risk factors for neutropenia and febrile neutropenia in patients with gastric or esophagogastric junction cancer receiving weekly paclitaxel and ramucirumab therapy: a single center retrospective study

BackgroundWeekly paclitaxel + ramucirumab (wPTX + RAM) therapy is recommended as the standard second-line chemotherapy regimen for unresectable advanced/recurrent gastric cancer (GC) or esophagogastric junction cancer. Recent subgroup analysis of the RAINBOW trial revealed a higher frequency of severe neutropenia due to wPTX + RAM in Japanese compared to Western patients. However, no risk factors for severe neutropenia have been identified.MethodsThis retrospective observational study included patients with advanced/unresectable gastric or esophagogastric junction cancer who received wPTX + RAM after failure to respond to platinum and fluoropyrimidine doublet chemotherapy between June 2015 and April 2020. We conducted multivariable logistic regression analyses to identify the risk factors associated with grade 4 neutropenia and febrile neutropenia (FN). In addition, we investigated the relationship between the number of risk factors and overall survival (OS) and progression-free survival (PFS).ResultsAmong 66 patients who met the inclusion criteria, grade 4 neutropenia and FN occurred in 21 (31.8%) and 12 (18.2%) patients, respectively. Prior treatment with oxaliplatin-containing regimens was identified as an independent risk factor for developing grade 4 neutropenia (odds ratio (OR) 20.034, 95% confidence interval (95% CI) 3.216–124.807, P = 0.001). Total bilirubin of > 1.5 mg/dL (OR 31.316, 95% CI 2.052–477.843, P = 0.013) and prior treatment with oxaliplatin-containing regimen (OR 12.502, 95% CI 1.141–137.022, P = 0.039) were identified as independent risk factors for developing FN. Next, we classified patients with 0, 1, 2 risk factor(s) as RF-0, RF-1, and RF-2 subgroups, respectively, and compared the PFS and OS among the three subgroups. PFS was not significantly different among the three subgroups, whereas OS was significantly shorter in the RF-2 subgroup (median 1.4 month, 95% CI 0.0–5.3 month) than in the RF-0 subgroup (median 10.2 month, 95% CI 6.8–13.5 month, P < 0.01 vs RF-2) and RF-1 subgroup (median 13.3 month, 95% CI 10.9–15.7 month, P < 0.01 vs RF-2).ConclusionsCareful monitoring for grade 4 neutropenia and FN is needed for patients receiving wPTX + RAM therapy who have a history of treatment with oxaliplatin-containing regimens and higher total bilirubin levels.

Traitement standard des stades III non résécables: Standard therapy for unresectable Stage III Non-Small Cell Lung Cancer

Approximately 25% of Non-small Cell Lung Cancer (NSCLC) present with a locally advanced disease. Stage III NSCLC includes heterogeneous diseases in term of initial clinical presentation and therapeutic strategy. An optimal initial staging integrating a PET/CT, EBUS mediastinal nodes exploration and an injected brain imaging is necessary. Pulmonary function test is to be systematically realized. The therapeutic strategy is decided in a multidisciplinary tumor board by an experimented team. Most of the stage IIIB and IIIC NSCLC receive a radio-chemotherapy. A concurrent plan is to be favored to a sequential plan. Platinum doublets comprise most standard chemotherapy regimens and must be started as early as possible. For fail or elderly patients who could not benefit from a concurrent chemotherapy, a sequential normo-fractionnated radiotherapy, or even a single chemotherapy are possible alternatives. After radio-chemotherapy, a consolidation systemic treatment by durvalumab, a checkpoint inhibitor, is currently a standard of care, in patients with a PD-L1 expressing tumor, based on the PACIFIC trial overall survival results.1877-1203/© 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Prospective Phase II Trial of Primary Lung Tumor Stereotactic Body Radiation Therapy (SBRT) Followed By Concurrent Mediastinal Chemoradiation and Adjuvant Immunotherapy for Locally-Advanced Non-Small Cell Lung Cancer (LA NSCLC)

To report the efficacy and toxicity outcomes of a prospective phase II trial of primary tumor SBRT followed by conventional chemoradiation to the lymph nodes and adjuvant immunotherapy in patients (pts) with unresectable LA NSCLC. Eligible pts included stage II-III LA NSCLC with peripheral primary tumors ≤ 7cm or centrally based tumors that had at least 2 cm separation from involved nodal disease. Pts received SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by standard radiation to 60 Gy in 30 fractions to the involved lymph nodes with concurrent platinum doublet chemotherapy. The trial was amended to allow pts without disease progression after chemoradiation to receive adjuvant durvalumab per the PACIFIC trial. The primary endpoint was 1 year progression free survival (PFS), evaluated as a binary variable. Frequencies and proportions were used for reporting this primary endpoint, in addition to adverse events and patterns of failure. Median PFS and OS were estimated using Kaplan Meier methods. Safety and efficacy is reported on the first 50 pts enrolled in the trial with a median follow-up of 24 months (mos) (range, 1-54 mos). Pts were primarily stage IIIA (60%) or stage IIIB (34%), with 6% of pts stage IIB. Overall grade 3 or higher toxicity related to SBRT and/or mediastinal radiation was 8% with two pts (4%) developing grade 3 pneumonitis and one pt having a grade 5 lung infection possibly related to radiation. Overall grade 2 pneumonitis related to SBRT or mediastinal radiation was 20%. Only one pt (2%) developed grade 3 esophagitis. No late cardiac events have been observed. The one-year PFS for all pts was 62% with a median PFS of 26.3 mos and median overall survival of 40.8 mos. Of the 50 pts enrolled, 37 received at least one dose of adjuvant durvalumab. The one-year PFS for pts who received at least one dose of durvalumab was 70.3% with a median PFS not yet reached in this group (median follow-up 24 mos). Patterns of failure were mostly distant with 26% of pts experiencing distant failure, 6% regional, and 2% distant and regional. There was only one local failure (2%) after SBRT in all 50 pts. SBRT to the primary tumor followed by conventional chemoradiation to the involved lymph nodes and adjuvant immunotherapy was well tolerated and showed improved 1-year PFS compared to prior conventional chemoradiation trials for locally advanced NSCLC. The results of this trial will be further evaluated in a randomized phase III study, NRG LU-008. Pts will receive either conventional chemoradiation vs. SBRT to the primary tumor followed by chemoradiation to the involved lymph nodes followed by consolidative immunotherapy to evaluate the possibility of utilization of SBRT as a new standard of care for LA NSCLC.

Daily Adaptive vs. Non-Adaptive External Beam Radiation Therapy with Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer (NSCLC): A Prospective Randomized Trial of an Individualized Approach for Toxicity Reduction (ARTIA-Lung)

Radiotherapy (RT) with concurrent chemotherapy is a standard treatment for Stage III NSCLC. However, radiation pneumonitis incidence increases rapidly with volume of lung irradiated, and esophagitis increases with dose to the esophagus. Both conditions can have adverse impacts on patients' quality of life. Daily online adaptive RT (ART) may allow for reduced normal tissue doses due to smaller margins around the target, as well as target size reduction with tumor response. This prospective, randomized controlled trial tests the hypothesis that the proportion of study participants who experience score ≥3 PRO-CTCAE cough, dyspnea, or dysphagia will be at least 20% lower with daily ART than with non-adapted RT. Enrollment goals are 244 subjects at up to 10 cancer centers worldwide. Eligibility criteria include stage IIIA-IIIC (AJCC v8) NSCLC; baseline grade 0-2 dyspnea, cough, and dysphagia; and no contralateral hilar or supraclavicular/cervical lymph node involvement. Subjects will be randomized (1:1) to CBCT-based daily ART or non-adapted RT using IMRT or VMAT delivering 60-66 Gy in 30-33 fractions with concurrent platinum doublet chemotherapy. Adjuvant immunotherapy with durvalumab is permitted. Follow-up for study participants will be for 1-year post-completion of chemoRT. Study endpoints include: frequency of PRO-CTCAE score ≥3 cough, dyspnea, or dysphagia from randomization to 30 days post-chemoRT; patient-reported quality of life (FACT-L and EQ-5D-5L questionnaires); percentage of lung receiving ≥20 Gy; mean doses to lung, heart, and esophagus; primary tumor response on CT or PET-CT (RECIST v1.1); local disease progression; and incidence of grade ≥2 pneumonitis within 1 year. Stratification factors are the treating institution and the presence of contralateral mediastinal lymph node metastases (associated with increased volume of irradiated lung). Interim analyses for futility and superiority will be performed when the primary endpoint data have been collected for 50% of evaluable participants. This study opened to enrollment on 20 October 2022 and is expected to be completed in approximately 3 years. This prospective, randomized clinical trial rigorously evaluates the impacts of daily online ART on radiation pneumonitis, esophagitis, and quality of life in patients with advanced NSCLC. It will collect standard tumor response and disease progression metrics to assure that reduced margins do not have an adverse impact on outcomes. Online ART is emerging as an innovative approach enabling increased sparing of normal tissues. The results of this clinical study will support evidence-based clinical decisions around ART technologies.

Explainable machine learning to inform real-world evidence: A case study on small cell lung cancer survival analysis.

113 Background: In recent years, machine learning algorithms for survival analysis have been developed as an alternative to traditional Cox regression. Despite the good performances, these are viewed as black box models that lack interpretability, which may limit their clinical applications. There has been a growing interest in explaining and interpreting machine learning models, which has led to the emergence of the field of explainable artificial intelligence (XAI). However, few studies have focused on how these methods could be of benefit to survival analysis of real-world healthcare data. Methods: In this study, we explored the use of current XAI techniques to analyze the effects of platinum doublet chemotherapy on small cell lung cancer patients in developed machine learning models.The analyzed data included real-world patients treated at Karolinska University Hospital (n=570) and three phase III randomized clinical trials shared by the Project Data Sphere initiative (n=987). The real-world data covariates included were age, sex, TNM staging, ECOG performance status, lab values, brain metastasis, and concomitant radiotherapy. The aggregated dataset including the clinical trials contained the following variables: age, sex, performance status, brain metastasis, and protocol violations. Eight machine learning models were trained and compared with Cox regression. The performance of the models was evaluated using C-index, and the time variation of Brier Score and C/D AUC.Temporal feature importance and partial dependence were used to explore the overall covariate impact on overall survival (Global XAI). Ceteris-paribus and SurvShap(t) were used to investigate the covariate impact for the single patient prediction (local XAI). The models were firstly trained only on real-world data before aggregation with the clinical trials. Results: Ensemble machine learning provided the best performances. XAI techniques showed the potential to increase explainability of survival predictions in function of time. Global XAI showed the time range of the model reliability, trend inversions regarding treatment decisions and covariate importance along the time. Local XAI allowed to test the impact of covariates between long survival patients and the comparison between real-world and clinical trials. Conclusions: Our results demonstrate the potential of XAI techniques applied to survival machine learning and real-world data, thus providing insights into the mechanisms driving model predictions and demonstrate the utility of this approach in clinical research.

Assessment of the clinicodemographic parameters and treatment outcomes of locally advanced and metastatic lung cancer cases – A retrospective study from northeast India

Background: There are many lacunae in our current understanding of the shifting epidemiological trends of lung cancer as well as lack of data among Northeast Indian patients. Aims and Objectives: This study tried to assess the clinicodemographic and treatment outcomes of advanced lung cancer cases. Materials and Methods: This was a retrospective hospital-based study. Patients with histopathologically confirmed locally advanced and metastatic lung cancer and were registered at Dr. Bhubaneswar Borooah Cancer Institute between January and December 2017 who were included in the study. A record was made of patient demographic-, clinical-, and treatment-related parameters. Kaplan–Meier survival curves were obtained. A two-tailed P&lt;0.05 was considered statistically significant. Results: Majority of the patients were elderly males (median=60 years), with a history of smoking in three quarter of them. Non-small-cell lung carcinoma (94%) type was the most common histology. About 93% of patients presented with TNM stage IV disease. The most common palliative chemotherapy (CT) regimen used was taxanes and platinum doublet (n=24, 35%). With a median follow-up of 6 months (range 0–37), the median progression-free survival and overall survival were 8 months and 10 months, respectively. The median survival was significantly longer in patients younger than 60 years. (13 months; P=0.021) and in those with non-small-cell histology (10 months). Conclusion: In this audit of resource-limited population with advanced lung cancer, palliative CT remains the mainstay of treatment. There is a further need to improve the survival of these advanced cases in a cost-effective manner.

Continuation ofosimertinib in EGFR-mutant non-small-cell lung cancer patients bearing CNS metastasis (EPONA study).

The patients harboring EGFR-mutated non-small-cell lung cancer, treated with EGFR tyrosine kinase inhibitor will lead to longer survival than those having non-small-cell lung cancer (NSCLC) patient who do not harbor EGFR mutations. This ongoing clinical trial is to investigate the secondary chemoprevention effect of osimertinib from CNS with platinum doublets chemotherapy in patients who had progressive disease outside of CNS lesions. The aim of this randomized, phase II trial is to evaluate platinum and pemetrexed chemotherapy followed by pemetrexed maintenance with or without continuation of osimertinib for secondary CNS prevention in patients with brain metastatic NSCLC with EGFR mutation, with other than CNS lesions, but no progressive disease in the CNS lesion after osimertinib. The primary end point is to assess progression-free survival by investigator assessment. The key secondary end points are overall survival, response rate, time to CNS controlling, time to whole-brain irradiation and safety. Clinical trial registration: Japan Registry of Clinical Trials (jRCT), Japan (jRCTs071200029).

Adjuvant chemotherapy in nasopharyngeal carcinoma

The value of adjuvant chemotherapy after definitive radiotherapy in locoregionally advanced nasopharyngeal carcinoma has been debated since the landmark publication of the Intergroup-0099 trial. 1 Al-Sarraf M LeBlanc M Giri PG et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol. 1998; 16: 1310-1317 Crossref PubMed Google Scholar The differing views occur for two reasons: (1) early chemoradiotherapy trials in the 2000s investigated various platinum-based regimens of concurrent chemoradiotherapy alone or in combination with adjuvant chemotherapy, with both strategies showing survival benefits over radiotherapy alone; and (2) it was generally observed that platinum doublet adjuvant chemotherapy after concurrent chemoradiotherapy was poorly tolerated. 2 Chua MLK Wee JTS Hui EP Chan ATC Nasopharyngeal carcinoma. Lancet. 2016; 387: 1012-1024 Summary Full Text Full Text PDF PubMed Scopus (934) Google Scholar The resistance towards recommending adjuvant chemotherapy to patients in the clinic was compounded after a phase 3 trial in China showed that adjuvant cisplatin–fluorouracil chemotherapy did not significantly improve failure-free survival after concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma compared with concurrent chemoradiotherapy alone. 3 Chen L Hu CS Chen XZ et al. Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial. Lancet Oncol. 2012; 13: 163-171 Summary Full Text Full Text PDF PubMed Scopus (432) Google Scholar Concurrent chemoradiotherapy followed by adjuvant cisplatin–gemcitabine versus cisplatin–fluorouracil chemotherapy for N2–3 nasopharyngeal carcinoma: a multicentre, open-label, randomised, controlled, phase 3 trialOur findings suggest that concurrent adjuvant cisplatin–gemcitabine could be used as an adjuvant therapy in the treatment of patients with N2–3 nasopharyngeal carcinoma, although long-term follow-up is required to confirm the optimal therapeutic ratio. Full-Text PDF

Association of docetaxel efficacy with cancer gene mutation status in patients with metastatic non-small-cell lung cancer who progressed on platinum doublets and immunotherapy.

e21030 Background: Docetaxel +/- ramucirumab remains the standard of care therapy after progression on platinum doublet and immune checkpoint blockade (ICB) in patients with metastatic non-small cell lung cancer (NSCLC). However, the clinical benefit from docetaxel is short-lived with substantial toxicity. Additionally, whether cancer gene mutation status impacts the benefit from docetaxel has not been systemically studied. In this real-world study, we aim to investigate whether cancer gene mutation status is associated with benefit from docetaxel. We also explored whether IMPOWER150-based regimens (ABCP-atezolizumab + bevacizumab + carboplatin + paclitaxel; ACP-atezolizumab + carboplatin + paclitaxel; BCP-bevacizumab + carboplatin+paclitaxel) may serve as alternative options with better efficacy in this patient population. Methods: We retrospectively queried MD Anderson Cancer Center GEMINI database for patients with metastatic NSCLC who received docetaxel, docetaxel+ramucirumab, or one of the above-mentioned IMPOWER150-based regimens after progression on concomitant or sequential platinum-doublet and ICI. Primary endpoints include progression-free survival (PFS) and overall survival (OS). Results: 274 patients were analyzed (docetaxel n = 99; docetaxel +ramucirumab n = 142; ABCP n = 28; BCP n = 4, ACP n = 1). No significant difference was observed in mPFS (3.00m versus 3.93m, P = 0.156) or mOS (8.40m vs.8.67m, P = 0.737) between patients from docetaxel monotherapy group and docetaxel+ ramucirumab group. Cancer gene mutations in EGFR, KRAS, TP53 or PD-L1 expression (0-1%; 1-49%; ≥50%) were not associated with PFS or OS in the 241 patients treated with docetaxel +/- ramucirumab. Furthermore, there was no difference in mPFS (5.50m versus 3.47m, P = 0.516) or mOS (10.40m versus 8.83m, P = 0.737) in patients who received IMPOWER 150-based regimens compared to those who were treated with docetaxel+/- ramucirumab. The median treatment duration was 1.60m (0.70m-20.23m), 1.90m (0.70m-32.90m), 4.80m(0.70m-33.47m) and 11 patients (11.11%), 20 patients (14.08%), and 3 patients (9.09%) discontinued treatment due to adverse events in the patients treated with docetaxel monotherapy, docetaxel+ramucirumab combined therapy, and the IMPOWER150 regimens, respectively. Conclusions: These results from this real-world study suggested that unlike for ICI therapy, where onco-driver mutations have profound impact on the clinical benefit, the cancer gene mutation status does not impact the benefit from docetaxel +/- ramucirumab in NSCLC patients who progressed on platinum doublets and ICI. Furthermore, the clinical benefit from docetaxel +/- ramucirumab is short-lived. Novel treatment regimens are urgently needed in this clinical setting.

Safety, efficacy and biomarker data in patients with non-small cell lung cancer treated with the anti-IL1RAP antibody nadunolimab in combination with platinum doublet.

9089 Background: Interleukin-1 Receptor Accessory Protein (IL1RAP), expressed in various tumors, is essential for IL-1α and IL-1β signaling. IL-1α/IL-1β are implicated in tumor progression and therapy resistance, and chemotherapy can upregulate IL-1α in e.g. non-small cell lung cancer (NSCLC). Nadunolimab (CAN04), a fully humanized ADCC-enhanced IgG1 antibody, targets IL1RAP and blocks IL-1α/IL-1β signaling. Here, data are reported from clinical phase 1/2 trials in NSCLC pts given nadunolimab and platinum doublet. Methods: Pts with advanced NSCLC, 1st line or progressed on pembrolizumab, received nadunolimab at 1 (n=16), 2.5 (n=3) or 5 mg/kg (n=11) with cisplatin/gemcitabine (NCG), or at 2.5 mg/kg with carboplatin/pemetrexed (NCP) (n=5). Four additional pts, 3rd line or beyond, received NCG at 1 or 1.75 mg/kg nadunolimab. Primary objective was safety; efficacy was evaluated as a secondary objective and effects on serum and tumor tissue biomarkers explored. Results: The 30 1st or 2nd line pts given NCG had a median PFS of 7.2 months (95% CI 5.5-8.2), ORR of 53% (34-72) and DoR of 5.8 months (3.7-7.5). A dose-response trend was observed for PFS and DoR (Table). Twenty non-progressing pts continued nadunolimab as monotherapy post chemo; 8 of these remained in disease control for a further 12-131 wks. Nadunolimab monotherapy was well tolerated with ≥grade 3 adverse events reported less frequently. Two pts (non-squamous, 2nd line post pembrolizumab) showed complete responses, one observed after &gt;40 wks of nadunolimab monotherapy. Furthermore, confirmed partial responses were observed in 3 of 5 pts given NCP, and 2 of 4 3rd line or beyond pts given NCG. NCG reduced several serum markers, e.g. CRP and tumor-promoting HGF, effects which were maintained by nadunolimab monotherapy. Additionally, a decrease of MCP-3 and 4 was observed during monotherapy. NCG also reduced IL-1- and tumor microenvironment (TME)-related markers in serum (angiopoietin 1, CXCL5, IL-8, TWEAK and VEGFA). Spatial analyses of protein and RNA markers in tumor biopsies are ongoing to verify potential effects in the TME. Conclusions: NCG shows promising efficacy in NSCLC with a trend for dose response, and long-term disease control by nadunolimab monotherapy post chemo with good safety. These observations are supported by changes in TME-related serum biomarkers. Preliminary data suggest similar efficacy with NCP, and in more heavily pretreated pts. Clinical trial information: NCT03267316 , NCT05116891 . [Table: see text]

A phase 1 first-in-human study of interferon beta (IFNβ) and membrane-stable CD40L expressing oncolytic virus (MEM-288) in solid tumors including non–small-cell lung cancer (NSCLC).

2569 Background: MEM-288 is a conditionally-replicative oncolytic adenovirus expressing human IFNβ and a recombinant membrane-stable form of CD40L (MEM40). Preclinical studies show MEM-288 induces robust dendritic cell-mediated systemic T cell responses capable of inhibiting abscopal tumor growth as monotherapy and synergizes with immune checkpoint inhibitors (ICI). Methods: MEM-288 is being evaluated in this Phase 1 open-label trial (NCT05076760) in pts with select solid tumors including NSCLC (a) refractory to standard therapy and (b) with a tumor lesion deemed feasible for biopsy and MEM-288 intratumoral (i.t.) injection. The primary objective is to determine using a BOIN design a recommended phase II dose of MEM-288 across 3 dose levels (DL1-3) spanning 1e10 to 1e11 viral particles by i.t. injection once every 3 weeks. Secondary objectives include efficacy assessment, including response rate of injected and non-injected tumors assessed separately. Tumor biopsies obtained immediately prior to the 1st and 2nd injections are used to explore biomarkers and anti-tumor immune responses. Results: As of February 2023, 12 pts (11 NSCLC and 1 pancreatic cancer; n = 3 DL1, n = 5 DL2, n = 4 DL3) have enrolled. The median number of MEM-288 i.t. injections was 2 (1-3), median age was 63 (39-76), and median prior lines of therapy was 3 (1-5). Radiology-guided injections were administered in superficial/palpable tumors and visceral lesions. No dose limiting toxicities occurred. Treatment-related adverse events observed in &gt; 1 pt include grade 1 injection site reaction (42%) and chills (17%). Of 10 response-evaluable pts, 4 (40%) pts had shrinkage of injected tumor (range -26 to -54%): 3 (30%) PR and 1 (10%) SD. Multiple pts also had stabilization or shrinkage of distal non-injected lesions. Best overall response was 3 (30%) stable disease and 7 (70%) progressive disease. After a single MEM-288 injection, biopsies show decreased tumor cell percentage concomitant with substantial increases in overall CD8+ T cells, increased T clonotype diversity in both tumor and peripheral blood, and increased TCF1+ stem-like CD8+ T cells that are strongly associated with response to ICIs. Plasma cytokine analysis showed increases in IFNg and of IFN-inducible cytokines and chemokines, supportive of stimulation of systemic response after MEM-288. Of note, a pt with strong stimulation of tumor and systemic T cell immunity after MEM-288 had subsequent CR (ongoing &gt; 7 months) to docetaxel + ramucirumab following prior treatment failure with platinum doublet + ICI received before MEM-288. Conclusions: Preliminary safety, antitumor and immune response data are encouraging. Updated results and immune data from this study will be presented. An expansion arm is planned with combination MEM-288 and anti-PD1 antibody in pts with advanced NSCLC refractory to ICI. Clinical trial information: NCT05076760 .

Clinical outcomes of chemotherapy rechallenge in patients with metastatic non-small cell lung (NSCLC) who progressed on immunotherapy maintenance after front line platinum doublets and immunotherapy.

e21205 Background: Maintenance immunotherapy (IO) is commonly utilized in metastatic NSCLC patients (pts) who did not progress after initial treatment with platinum doublet and IO. Upon progression, docetaxel with or without ramucirumab remains the treatment of choice, which is associated with poor response and high toxicity. We explored the option of rechallenge of original chemotherapy agents in this patient population. Methods: We queried MD Anderson Cancer Center GEMINI database to perform a retrospective review in pts who received chemotherapy (chemo) rechallenge with or without IO after progression on or after IO maintenance from 03/2016 – 12/2022 at MD Anderson Cancer Center. We assessed clinical response and progression free survival (PFS) with initial triplet treatment and rechallenge with chemotherapy. Clinical response was defined as clinical benefit based on clinician’s radiographic and clinical assessment. PFS was defined as the time interval free of disease progression. Demographics and results were summarized with descriptive statistics. Results: 20 patients received chemo rechallenge with or without IO after progression on IO maintenance. Upon chemo rechallenge, 7 pts received pemetrexed; 10 pts (50%) received carboplatin and pemetrexed; 19 pt received chemo rechallenge with IO. Median duration of initial IO maintenance was 9.4 months. Median duration of chemo rechallenge was 5.2 months. 10 (50%) pts discontinued chemo due to progression after receiving chemo rechallenge; 2 (10%) pts discontinued chemo rechallenge due to toxicities; 3 (15%) pts remained on therapy at the data cutoff of 2/10/2023. Median PFS with initial triplet was 14.3 months. Median PFS with chemo rechallenge was 7.4 months, longer than the histological control of 3-5 months from docetaxel +/- ramucirumab. Conclusions: Our single center retrospective review demonstrated that chemo rechallenge after progression on IO maintenance post front-line chemo-IO therapy had good tolerability and reasonable PFS, which may offer a reasonable alternative option to docetaxel+/-ramucirumab. Future studies are needed to confirm this result using docetaxel +/- ramucirumab as a control. [Table: see text]

Final results of a phase II trial of prolgolimab with platinum-based therapy and bevacizumab in patients with advanced cervical cancer.

5536 Background: Here we present the final results of single-arm phase II CAESURA (NCT03912402) study of prolgolimab (anti-PD-1 antibody) with platinum doublet and bevacizumab in subjects with advanced cervical cancer (CC). Methods: 58 patients (pts) with metastatic or recurrent/persistent CC with measurable disease received prolgolimab (3 mg/kg) Q3W together with paclitaxel, platinum drug (cis- or carboplatin) and bevacizumab for 6 cycles and then therapy with prolgolimab and bevacizumab until disease progression or toxicity. Objective response rate (ORR) was assessed by central radiology review per RECIST 1.1 (primary endpoint) and iRECIST criteria. CT scans were performed after 9 and 18 weeks of treatment and in case of suspicion on disease progression. Results: Distant metastases at screening had 42 pts, 16 had recurrent or persistent CC. The median age of pts was 48 [38; 58] years old. Squamous cell carcinoma was diagnosed in 50 of 58 subjects. PD-L1 CPS ≥ 1 (22C3) was found in 45 pts, CPS &lt; 1 in 6 cases. ORR per RECIST 1.1 was 63.8% (37 of 58 pts) and included 2 complete, 35 partial responses. ORR per iRECIST was 70.7% (41 of 58 pts) with 2 complete and 39 partial responses. At the cut-off date (12 months) PFS (secondary endpoint) per RECIST 1.1 criteria counted 8.5 (95% CI 5.7; 10.9) months, per iRECIST criteria it reached 13.1 (95% CI 8.1; 13.6) months. Median overall survival was not reached. Any grade adverse events (AEs) occurred in 98% (57/58) of pts, of them in 69% (40/58) they were related to study treatment, including 12 cases of severe events (gr. 3 or higher). Immune-related AEs (irAEs) occurred in 38% (22/58) of pts. The most common irAEs were gr. 1–2 endocrine disorders (26%), including thyroid disorders and one case of gr. 2 adrenal insufficiency. Other important irAEs included 2 cases of enterocolitis (gr. 3 and 4), 1 case of dermatitis (gr. 3), several cases of gr. 2–3 transaminase elevation (9%). In 15 pts at least one component of study treatment was discontinued due to AE, of them 4 events were related to study treatment (including immune-related enterocolitis and adrenal insufficiency). Conclusions: Prolgolimab in combination with chemotherapy and bevacizumab demonstrated promising efficacy, known and acceptable safety profile in pts with advanced CC. Phase III placebo-controlled trial evaluating prolgolimab with chemotherapy and bevacizumab (NCT03912415) as first-line therapy option in subjects with CC is ongoing. Clinical trial information: NCT03912402 .

How comparable are outcomes for approved PD-1/PD-L1 checkpoint inhibitors (CPI)? A model-informed drug development approach to answer the question.

e21152 Background: Treatment strategies in metastatic non-small cell lung cancer (mNSCLC) have been implemented by anti-PD-(L)1 based therapies. This work aimed to develop a model-based meta-analysis (MBMA) to compare ORR, median PFS (mPFS), median OS (mOS), and treatment-related adverse events Grade 3-5 (TRAEs Gr3+) among anti-PD-(L)1 therapies in mNSCLC. Methods: A curated database of phase 1, 2, and 3 study results in mNSCLC patients treated with at least one FDA-approved PD-(L)1 CPI was used for these analyses. The ORR, mPFS, mOS, and TRAEs Gr3+ analysis datasets included results from 40, 39, 35 and 45 studies, and represented 13324, 13220, 13029, and 21077 patients, respectively. Treatments included: platinum doublet (Pt), pembrolizumab (+/- Pt), nivolumab (+/- Pt and +/- ipilimumab), atezolizumab (+/- Pt), and cemiplimab. Models were developed to quantify drivers of variability on outcomes across trials (i.e., treatment, covariates, random effects). The following covariates were evaluated: PD-L1 expression, line of therapy, ECOG PS, histology, geography/race, sex, age, and smoking status. Results: Treatment naïve patients showed better efficacy than treatment experienced patients, while higher PD-L1 expression was associated with improvement for CPI-containing therapies. Asian-majority trials and patients with PS 0 achieved higher mOS. After adjusting for covariates, similar efficacy was observed across PD-(L)1 within both mono- and combination therapy groups (Table 1). No clinically meaningful covariates were identified for TRAEs Gr3+. Rates were comparable between chemotherapy +/- PD-(L)1, but lower for PD-(L)1 monotherapy. Conclusions: MBMA enables an appropriate comparison of CPI-containing therapy using published study results. To our knowledge, this is the first such analysis in mNSCLC comparing efficacy and safety across PD-(L)1 based therapies. Results suggest PD-(L)1 CPI have similar treatment outcomes in mNSCLC, and PD-L1 expression may be more impactful on clinical benefit of monotherapy compared to CPI combination with chemotherapy. [Table: see text]

Patterns of ovarian cancer care in an elderly population in Australia: A prospective cohort study from the National Gynaecology Oncology Registry (NGOR).

5572 Background: Elderly women with ovarian cancer are often undertreated in comparison to best practice. The National Gynae-Oncology Registry (NGOR) is Australia’s first country-wide clinical quality registry (CQR) measuring compliance with optimal care defined by a set of clinical quality indicators (CQIs). Objectives: To assess compliance with a predefined set of CQIs for elderly women with newly diagnosed ovarian cancer aged &gt; 75 compared to non-elderly women aged &lt;75 years of age from the NGOR sites. Methods: All women with newly diagnosed ovarian cancer from May 2017 – July 2022 were eligible for inclusion. Data were collected from medical records and relevant hospital linked databases by expert data managers. Results: A total of 1590 women were eligible for inclusion from 21 hospitals across 5 Australian states. The CQI data were subsequently aggregated and are summarised in the table. The proportion of elderly women receiving first-line chemotherapy with a platinum and taxane doublet was significantly lower compared to non-elderly (60% vs 89%, p &lt; 0.001). The proportion of women with sub-optimally debulked or Stage IV cancer who received first-line chemotherapy with a platinum/taxane doublet and bevacizumab was significantly lower in elderly women compared to non-elderly (10% vs 30%, p &lt; 0.001) . Enrolment in clinical trials or translational research was significantly lower in elderly women compared to non-elderly (13% vs 21%, p=0.002). The remaining CQIs showed no significant differences between the age groups. Conclusions: In this cohort, most measures of best practice were not significantly different between elderly and non-elderly women, with the exception of elderly women receiving less first line doublet chemotherapy, less doublet chemotherapy with bevacizumab in sub-optimally debulked or Stage IV cancer, and less likely to be enrolled in clinical trials or translational research. While these 3 CQIs represent a minority of the overall list of CQIs, such lack of compliance may result in significant differences in quality of life and overall survival for elderly women with ovarian cancer. Subsequent investigation is therefore warranted to confirm and explain these findings. [Table: see text]