First-line Immune Checkpoint Inhibitors Research Articles

Revalidation of the ATTRACTION-4 study in a real-world setting: a multicenter, retrospective propensity score matching study in China.

Immune-checkpoint inhibitors (ICIs) combined with chemotherapy have been successfully used in clinical trials to treat advanced gastric cancer. However, the efficacy and safety of first-line immunotherapy combined with chemotherapy in Chinese patients are unknown. This multicenter retrospective study included patients with human epidermal growth factor receptor-2 (HER-2) negative advanced gastric cancer treated with first-line chemotherapy or chemotherapy with an ICI between January 2019 and December 2022. Propensity score matching was used to compare progression-free survival (PFS), overall survival, objective response rates, and adverse reactions between cohorts. After propensity score matching, 138 patients, who had balanced baseline characteristics, were included in the chemotherapy and combination treatment groups. The median follow-up duration was 16.90 months, and the median PFS was 8.53 months (95% confidence interval [CI] 7.77-9.28) in the combination treatment group and 5.97 months (95% CI 4.56-7.37) in the chemotherapy group. The median survival duration was 17.05 months (95% CI 14.18-19.92) in the combination treatment group and 16.46 months (95% CI 12.99-19.93) in the chemotherapy group. The PFS subgroup analysis revealed that age ≥65 years, women, Eastern Cooperative Oncology Group performance status of 1, non-signet ring cell carcinoma, esophagogastric junction, liver metastasis, peritoneal metastasis, no massive ascites, only one metastatic organ, and combined platinum-based chemotherapy correlated with treatment benefit. The incidences of adverse events above grade 3 were comparable between groups. Our study confirmed the ATTRACTION-4 trial results. Compared with chemotherapy, first-line ICIs combined with chemotherapy prolonged PFS but did not improve overall survival in patients with HER-2-negative advanced gastric cancer.

Association between age and efficacy of first-line immunotherapy-based combination therapies for mRCC: a meta-analysis.

Aim: To compare the efficacy of first-line immune checkpoint inhibitor (ICI)-based combinations in metastatic renal cell carcinoma (mRCC) patients stratified by chronological age. Methods: According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, hazard ratios for overall survival (OS) from randomized controlled trials were synthesized. Results: Five RCTs were eligible for meta-analyses. ICI-based combinations significantly improved OS compared with sunitinib alone, both in younger (<65years) and older (≥65years) patients, whereas the OS benefit was significantly better in younger patients (p=0.007). ICI-based combinations did not improve OS in patients aged ≥75years. Treatment rankings showed age-related differential recommendations regarding improved OS. Conclusion: OS benefit from first-line ICI-based combinations was significantly greater in younger patients. Age-related differences could help enrich shared decision-making.

Network meta-analysis of first-line immune checkpoint inhibitor therapy in advanced non-squamous non-small cell lung cancer patients with PD-L1 expression ≥ 50%

IntroductionThe optimal first-line immunotherapy regimen for advanced non-squamous non-small cell lung cancer (NS-NSCLC) patients with programmed cell death ligand 1 (PD-L1) expression ≥ 50% remains unclear. Our aim is to determine the most effective treatment regimen through a network meta-analysis (NMA) comparing these treatments.MethodsA systematic search was performed in PubMed, Cochrane Library, Web of Science, and Embase databases, and a Bayesian network meta-analysis was conducted. To ensure transparency, the study was registered in the International Prospective Register of Systematic Reviews (CRD42022349712).ResultsThe analysis included 11 randomized controlled trials (RCTs) with 2037 patients and 12 immunotherapy combinations. ICI-ICI, ICI alone, and chemotherapy-ICI showed significant advantages over chemotherapy in terms of overall survival (OS) and progression-free survival (PFS). Pembrolizumab plus chemotherapy showed the best OS results compared to chemotherapy. Tislelizumab plus chemotherapy and sintilimab plus chemotherapy provided the best PFS results.ConclusionsFor NS-NSCLC patients with PD-L1 ≥ 50%, pembrolizumab plus chemotherapy, tislelizumab plus chemotherapy, and sintilimab plus chemotherapy are recommended as good treatment options based on the results of this Network meta-analysis (NMA).

Comparative analysis of immune-related adverse events among patients with melanoma on immune checkpoint inhibitors: A retrospective cohort study.

In a large, multi-institutional cohort of 672 patients with melanoma, we examined the comparative incidence and severity of immune-related adverse events among patients receiving first-line immune checkpoint inhibitors. Comparing PD-1 inhibitors, nivolumab was associated with significantly lower risk of high-grade toxicity onset compared with pembrolizumab on unadjusted logistic regression analysis. Compared with pembrolizumab, use of the CTLA-4 inhibitor ipilimumab was associated with a significant increase in risk of gastrointestinal, but not endocrine and cutaneous toxicities.

Assessing the role of colonic and other anatomical sites uptake by [18 F]FDG-PET/CT and immune-inflammatory peripheral blood indexes in patients with advanced non-small cell lung cancer treated with first-line immune checkpoint inhibitors.

Inflammation in non-small cell lung cancer (NSCLC) may impair the response to immune checkpoint inhibitors (ICIs) and can be indicated by peripheral blood inflammatory indexes. 2-deoxy-2-[18 F]fluoro-D-glucose positron emission tomography/computed tomography ([18 F] FDG-PET/CT) may be used as a marker of inflammation by measuring glucose metabolism in different colonic sites. This retrospective analysis aimed to investigate the correlation between [18 F] FDGPET/CT SUVratio in six gastrointestinal districts, the spleen, the pharynx and the larynx alongside the most avid tumor lesion with peripheral blood inflammatory indexes, including the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammatory index (SII, i.e., NLR times platelets) and lactate dehydrogenase (LDH), in patients with [18 F] FDG-PET/CT staged IV NSCLC who received first-line immune checkpoint inhibitors (ICIs). The role of SUVratios and peripheral blood inflammatory indexes in predicting overall survival (OS) and progression-free survival (PFS) was then explored. A total of 43 patients were treated with first-line ICI alone (58%) or in combination with chemotherapy (42%). A significant correlation was only found between the rectosigmoid SUVratio and NLR (p = 0.0465). NLR >5.5 and LDH > 333.5 were associated with a worse OS (p = 0.033 and p = 0.009, respectively). The SII was associated with a worse PFS in patients treated with ICI alone (p = 0.033). None of the SUVratios were significantly associated with OS or PFS, although a high left colon SUVratio showed a trend toward a worse PFS. There was no significant correlation between [18 F]FDG PET/CT uptake in different anatomical sites, and in the tumor, and systemic immune-inflammatory indexes. The prognostic role of high left colon SUVratio deserves further investigation.

Survival of patients with KRAS G12C mutated stage IV non-small cell lung cancer with and without brain metastases treated with immune checkpoint inhibitors

IntroductionFew data is available on whether brain metastases (BM) influence survival in patients with stage IV KRAS G12C mutated (KRAS G12C+ ) non-small cell lung cancer (NSCLC) treated with first-line immune checkpoint inhibitor (ICI) +/- chemotherapy ([chemo]-ICI). MethodsData was retrospectively collected from the population-based Netherlands Cancer Registry. The cumulative incidence of intracranial progression, overall survival (OS) and progression free survival (PFS) was determined for patients with KRAS G12C+ stage IV NSCLC diagnosed January 1 – June 30, 2019, treated with first-line (chemo)-ICI. OS and PFS were estimated using Kaplan-Meier methods and BM+ and BM− groups were compared using log-rank tests. ResultsOf 2489 patients with stage IV NSCLC, 153 patients had KRAS G12C+ and received first-line (chemo)-ICI. Of those patients, 35% (54/153) underwent brain imaging (CT and/or MRI), of which 85% (46/54) MRI. Half of the patients with brain imaging (56%; 30/54) had BM, concerning one-fifth (20%; 30/153) of all patients, of which 67% was symptomatic. Compared to BM−, patients with BM+ were younger and had more organs affected with metastasis. Around one-third (30%) of patients with BM+ had ≥5 BM at diagnosis. Three quarters of patients with BM+ received cranial radiotherapy prior to start of (chemo)-ICI. The 1-year cumulative incidence of intracranial progression was 33% for patients with known baseline BM and 7% for those without (p = 0.0001). Median PFS was 6.6 (95% CI 3.0–15.9) and 6.7 (95% CI 5.1–8.5) months for BM+ and BM− (p = 0.80), respectively. Median OS was 15.7 (95% CI 6.2–27.3) and 17.8 (95% CI 13.4–22.0) months for BM+ and BM− (p = 0.77), respectively. ConclusionBaseline BM are common in patients with metastatic KRAS G12C+ NSCLC. During (chemo)-ICI treatment, intracranial progression was more frequent in patients with known baseline BM, justifying regular imaging during treatment. In our study, presence of known baseline BM did not influence OS or PFS.

Tumor monocyte content predicts immunochemotherapy outcomes in esophageal adenocarcinoma.

For inoperable esophageal adenocarcinoma (EAC), identifying patients likely to benefit from recently approved immunochemotherapy (ICI+CTX) treatments remains a key challenge. We address this using a uniquely designed window-of-opportunity trial (LUD2015-005), in which 35 inoperable EAC patients received first-line immune checkpoint inhibitors for four weeks (ICI-4W), followed by ICI+CTX. Comprehensive biomarker profiling, including generation of a 65,000-cell single-cell RNA-sequencing atlas of esophageal cancer, as well as multi-timepoint transcriptomic profiling of EAC during ICI-4W, reveals a novel Tcell inflammation signature (INCITE) whose upregulation correlates with ICI-induced tumor shrinkage. Deconvolution of pre-treatment gastro-esophageal cancer transcriptomes using our single-cell atlas identifies high tumor monocyte content (TMC) as an unexpected ICI+CTX-specific predictor of greater overall survival (OS) in LUD2015-005 patients and of ICI response in prevalent gastric cancer subtypes from independent cohorts. Tumor mutational burden is an additional independent and additive predictor of LUD2015-005 OS. TMC can improve patient selection for emerging ICI+CTX therapies in gastro-esophageal cancer.

Treatment-Free Survival After Nivolumab vs Pembrolizumab vs Nivolumab-Ipilimumab for Advanced Melanoma

Treatment-free survival (TFS) represents an alternative time-to-event end point, accurately characterizing time spent free of systemic therapy, providing a more patient-centric view of immune checkpoint inhibitor (ICI) therapy regimens. There remains a lack of studies evaluating TFS outcomes among patients with advanced melanoma who are receiving immunotherapy, especially outside of the clinical trial setting. To evaluate TFS outcomes for patients with advanced melanoma receiving first-line ICI therapy outside of a clinical trial setting. This multicenter cohort study of patients with advanced melanoma receiving first-line ICI therapy between August 1, 2013, and May 31, 2020, was conducted in Alberta, Canada. Data analysis was performed in August 2022. Patients received standard-of-care, first-line ICI therapy treatment regimens including single-agent nivolumab, single-agent pembrolizumab, or ipilimumab-nivolumab. Treatment-free survival was defined as the difference in the 36-month restricted mean survival time between 2 conventional survival end points: (1) time from treatment initiation to ICI cessation, death, or censoring at last follow-up and (2) time from treatment initiation to subsequent systemic anticancer therapy, death, or censoring at last follow-up. A total of 316 patients with advanced melanoma receiving first-line nivolumab (n = 51; median age, 66 years [IQR, 56-78 years]; 31 men [60.8%]), pembrolizumab (n = 158; median age, 69 years [IQR, 60-78 years]; 112 men [70.9%]), or combination nivolumab-ipilimumab (n = 107; median age, 53 years [IQR, 42-60 years]; 72 men [67.3%]) were included. Treatment groups were similar with regard to sex, primary tumor location, and presence of metastasis, although patients receiving combination nivolumab-ipilimumab had a lower Eastern Cooperative Oncology Group status, were younger, and were more likely to be BRAF V600E positive than those receiving anti-programmed cell death protein 1 (anti-PD-1) monotherapy. The restricted mean TFS was longer for nivolumab-ipilimumab (12.4 months [95% CI, 8.8-16.0 months]) compared with nivolumab (8.9 months [95% CI, 4.4-13.5 months]) and pembrolizumab (11.1 months [95% CI, 8.5-13.8 months]). During the 36-month follow-up interval, patients treated with nivolumab-ipilimumab spent 34.4% of their time (12.4 of 36 months) not receiving systemic anticancer treatments compared with 30.8% (11.1 of 36 months) and 24.7% (8.9 of 36 months) of the time for the pembrolizumab and nivolumab treatment groups, respectively. This cohort study of patients with advanced melanoma receiving first-line ICI therapy suggests that TFS represents a patient-centric, informative end point. Patients treated with combination nivolumab-ipilimumab spent more time alive and free from systemic anticancer therapy than those treated with anti-PD-1 monotherapy alone.

Better Late Than Never: The Impact of Steroidal Treatment on the Outcome of Melanoma Patients Treated with Immunotherapy.

Successful treatment with Immune Checkpoint Inhibitors (ICI) requires the balanced activation of the immune system. Over-activation may result in immune-related adverse events (irAEs), which often require steroidal treatment. This study examined the possible impact of steroids on treatment efficacy in melanoma patients concerning initiation timing and dosage. A retrospective, single-center analysis of patients with advanced melanoma who underwent first-line ICI therapy during 2014-2020 was conducted. Among the 415 patients, two-hundred patients (48.3%) were exposed to steroids during the first line, most of them due to irAEs (n = 169, 84.5%). Nearly a quarter of them were exposed to steroids within the first four weeks of treatment. Surprisingly, steroidal exposure was associated with better progression-free survival (PFS; HR = 0.74, p = 0.015); however, early exposure (within four weeks of treatment) resulted in a significantly shorter PFS compared to late exposure (adjusted HR 3.2, p < 0.001). Early exposure to corticosteroids during the priming phase of ICI therapy could impede the establishment of an effective immune response. These results suggest that caution should be exercised when considering the use of steroids for the management of early-onset irAEs.

Impact of PD-L1 and KRAS status on the efficacy of nintedanib (NIN) + docetaxel (DOC) following treatment with first-line immune checkpoint inhibitor (ICI) + chemotherapy in patients with adenocarcinoma NSCLC: Analysis of cohort C of the non-interventional VARGADO trial.

e21149 Background: The identification of targetable molecular tumor markers in patients (pts) with NSCLC has increased significantly over the past decades and has resulted in important changes to individual treatment approaches. One such marker is KRASG12C for which a specific treatment is now available following prior systemic therapy. While ICIs ± chemotherapy represent first-line (1L) standard of care, the sequence of subsequent effective therapies still needs to be investigated. Methods: Cohort C of the ongoing, prospective, non-interventional VARGADO study (NCT02392455) is investigating the combination of NIN + DOC as second-line (2L) treatment after prior 1L ICI + chemotherapy in pts with adenocarcinoma NSCLC. This updated analysis of Cohort C focuses on the safety and efficacy of NIN + DOC according to programmed death ligand-1 (PD-L1) and KRAS status. Results: At the cut-off date (December 1, 2022) 219 pts have been enrolled to Cohort C. Median age was 64 years (range: 37–84) and 58.9% (129/219) of pts were men. At baseline, 30.6% (67/219) were ECOG PS 0 and 50.2% (110/219) were ECOG PS 1. 88.1% (193/219) had stage IV disease. Brain metastases were present in 19.2% (42/219) of pts and 88.1% (193/219) had received prior 1L pembrolizumab-based combination therapy. In the overall population, median PFS was 4.5 months (mo; 95% CI: 3.6–5.3, 219 pts) and median OS was 9.6 mo (95% CI: 6.5–11.2, 217 pts) with NIN + DOC. KRAS mutation status has been documented for 119 pts. In KRAS wild-type pts (75/119), median PFS was 3.7 mo (95% CI: 2.6–5.3) and median OS was 7.7 mo (95% CI: 5.2-11.2). In KRAS mutation-positive pts (44/119) median PFS was 5.1 mo (95% CI: 3.4–6.3) and median OS was 6.7 mo (95% CI: 5.3–15.1). In 33 pts with a non-G12C KRAS mutation, median PFS was 5.0 mo (95% CI: 3.4–6.7) and median OS was 6.7 mo (95% CI: 5.3–15.1). ORR was 20.0% (15/75), 25.0% (11/44), 27.3% (9/33) and 18.2% (2/11) in pts with KRAS wild-type, KRAS mutated, non-G12C mutated and G12C mutated status, respectively. The corresponding disease control rates (DCR) were 45.3% (34/75), 47.7% (21/44), 48.5% (16/33) and 45.5% (5/11). PD-L1 status prior to 1L therapy was &lt; 1% in 86 pts and ≥1% in 76 pts and did not impact OS (median 10.6 mo [95% CI: 6.5–15.1] and 10.5 mo [95% CI: 5.7–12.5], respectively) or DCR (51.2% and 51.3%, respectively) with NIN + DOC. The most frequent NIN-related adverse events of any grade in the overall population were diarrhea 34.7% (76/219), nausea 14.2% (31/219), vomiting 8.2% (18/219) and fatigue 7.8% (17/219). Conclusions: NIN + DOC is an effective and safe 2L treatment option after prior 1L ICI + chemotherapy for NSCLC adenocarcinoma pts independent of PD-L1 and KRAS status. Clinical trial information: NCT02392455 .

Models including pathological and radiomic features vs clinical models in predicting outcome of patients with metastatic non-small cell lung cancer treated with immunotherapy.

e21164 Background: Overall survival of patients with metastatic non-small cell lung cancer (NSCLC) has increased with the use of anti-PD-1 immune checkpoint inhibitors. However, the duration of response remains highly variable between patients, and only 20-30% of patients are alive at 2 years. Thus, new biomarkers for predicting response to treatment and patient outcomes are still needed to guide therapeutic decision. In this study, we retrospectively investigated multimodal approaches that might improve the limited predictive power of clinical data. Methods: We studied a cohort of 317 patients with metastatic NSCLC treated with first-line immune checkpoint inhibitors alone or combined with platinum-based chemotherapy. Clinical data were collected for all patients, pathological slides (HES and PD-L1 staining) and baseline 18-FDG PET/CT scans were available in 237 and 130 patients respectively. An automatic cell type detection algorithm was applied to each pathological slide and pathomic features were extracted from the resulting annotations. After semi-automated segmentation of all tumor foci in the PET/CT scans, radiomic features were calculated for each tumor lesion and aggregated across all the lesions of each patient. Prognostic models were built using random forest and XGboost classifiers to predict patient survival at 12 months based on 1) features from single modalities (clinical, pathomic, or radiomic), 2) features from multiple modalities, where early fusion and late fusion strategies were investigated. The models were trained and tested with cross-validation and their performances were established using the area under the ROC curve (AUC) computed on the same 88 test patients for whom all the modalities were available. Results: Unimodal strategies yielded AUC of 0.62 ± 0.08 (1 std), 0.64 ± 0.07, 0.59 ± 0.08 for clinical, radiomic and pathomic features respectively. With late fusion, bimodal models consistently outperformed the clinical model, with the combination of radiomic and clinical features giving the best performance (AUC = 0.67 ± 0.07). The trimodal model outperformed all other modality combinations with an AUC of 0.69 ± 0.07; in particular, it was significantly superior to the clinical model (p-value &lt; 0.001, paired t-test). The early fusion experiments confirmed the superiority of every bimodal approach over the clinical model. However, the trimodal model did not outperform the best bimodal model with early fusion. Validation will be performed on independent cohorts from external centers. Conclusions: Our study highlighted the potential of multimodal approaches for predicting the outcome of metastatic NSCLC patients treated with immunotherapy. Models integrating medical images and pathological slides usually collected from routine care outperformed a model trained on clinical data alone.

First-line immune checkpoint inhibitors alone or in combination with chemotherapy in real-life elderly patients with advanced non-small cell lung cancer (NEJ057).

9012 Background: Immune checkpoint inhibitor (ICI) plus chemotherapy is now a standard treatment for non-small cell lung cancer (NSCLC) without targetable oncogene alternations. However, the efficacy and safety of ICI plus chemotherapy (ICI-chemo) in 75 years or older patients have not been elucidated. The aim of this study is to reveal the real-world choice of first-line drugs in elderly patients (pts) and evaluate the efficacy and safety of ICI-chemo. Methods: We conducted a multicenter (58 centers in Japan), retrospective cohort study of consecutive 75 years or older pts with clinical stage IIIB, IIIC, IV, postoperative or radiotherapy recurrent NSCLC who started first-line systemic therapy between December 2018 and March 2021. Pts with epidermal growth factor receptor mutations, anaplastic lymphoma kinase rearrangements, or whose first-line systemic therapy was molecular targeted therapy were excluded. Results: A total of 1245 pts were enrolled: median (range) age 78 (75-95) years; 278 (22%) female; 367 (29%) ECOG PS 0, 680 (55%) PS 1 and 171 (14%) PS 2; 678 (54%) adenocarcinoma; PD-L1 tumor proportion score 268 (22%) &lt;1%, 387 (31%) 1-49% and 410 (34%) ≥50%; 354 (28%) ICI-chemo, 425 (34%) ICI alone, 311 (25%) platinum-doublet chemotherapy and 155 (12%) single agent chemotherapy. The median overall survival (OS) was 20.0 months (95%CI, 17.1–23.6) in the ICI-chemo group, 19.8 months (95%CI, 16.5–23.8) in the ICI alone group, 12.8 months (95%CI, 10.7–15.6) in the platinum-doublet chemotherapy group and 9.5 months (95%CI, 7.4–13.4) in the single agent chemotherapy group, respectively. After propensity score matching, there was no difference in OS and progression-free survival (PFS) between ICI-chemo group (n=96) and ICI alone group (n=95) in PD-L1 ≥1% (OS: HR, 0.98; 95% CI, 0.67-1.42, PFS: HR, 0.92; 95% CI, 0.67-1.25). Regardless of PD-L1 subgroups (1-49% or ≥50%), no significant differences in OS and PFS were observed. Concerning safety, Grade 3 or higher immune-related adverse events (irAEs) occurred in 86 pts (24.3%) in the ICI-chemo group and 76 pts (17.9%) in the ICI alone group (p = 0.03). The number of pts who required steroids for irAEs was 115 (32.5%) in the ICI-chemo group and 105 (24.7%) in the ICI alone group (p = 0.02). Pneumonitis was reported in 83 pts (23.4%) in the ICI-chemo group and 66 pts (15.6%) in the ICI alone group (p = 0.006). Conclusions: In real-world data for pts aged 75 years or older, ICI-chemo did not improve survival and increased the incidence of grade 3 or higher irAEs compared to ICI alone. Based on our results, ICI alone is recommended for elderly pts with PD-L1 positive NSCLC. Clinical trial information: UMIN000046700 .

Time to treatment initiation in a retrospective cohort of patients with advanced lung cancer treated with an immune checkpoint inhibitor.

e21199 Background: Advanced lung cancer is diagnosed by imaging through screening, incidental findings, or during the workup of symptoms. Historically, there was no apparent benefit in expediting the times to biopsy, staging, and chemotherapy initiation. However, the widespread first-line use of immune checkpoint inhibitors (ICIs) can introduce delays such as biomarker testing and financial approval. We aimed to test whether the time to ICI treatment initiation was associated with worse clinical outcomes. Methods: We created a retrospective registry of all patients with advanced lung cancer who received at least one dose of an ICI for any first-line indication between 2/1/2011 and 4/7/2022 at a comprehensive cancer center and its outreach clinics and made a validated database. We defined the time to biopsy as the interval between the initial diagnostic imaging of the index cancer and the biopsy. We defined time to treatment initiation (TTI) as the interval between initial imaging and the first dose of ICI. Overall survival was the interval from the biopsy date to death. We used a Cox multivariate regression to model the continuous association of each additional month of TTI with survival. Confidence intervals (CI) were calculated to 95%, and p-values &lt; 0.05 were considered significant. The study had institutional IRB approval. Results: Our cohort consisted of 472 patients diagnosed with advanced lung cancer and treated with first-line ICI. The median time to biopsy was 15.5 days with an interquartile range (IQR) of 5-29 days, median TTI was 51 days (IQR 35-79), and median overall survival was 14.3 months (CI 11.5-16.6). TTI was not associated with survival by unadjusted or multivariate analysis (HR 0.98, CI 0.95-1.01 and HR 1.02, CI 1.00-1.05, respectively). Smoking history (HR 1.011, CI 1.00-1.02 per pack-year) and higher pre-treatment ECOG performance scores (p &lt; 0.01) were associated with worse survival. Tumor histologic subtype, autoimmune comorbidities, and toxic dust exposure were not associated with survival. The time to biopsy was not associated with survival by unadjusted or multivariate analysis (HR 0.97, CI 0.95-1.01, and HR 1.02, CI 0.97-1.07, for each additional week). Among the subset of patients with a symptomatic presentation of cancer (n = 363, 77%), longer TTI was associated with improved survival, but this effect became non-significant in multivariate analysis (HR 0.94, CI 0.89-0.99 and HR 0.96, CI 0.86-1.08, respectively). Conclusions: We did not find evidence that a shorter TTI is associated with improved survival among patients with advanced lung cancer starting first-line ICI. Additional studies are needed to test if baseline disease burden or other clinical factors can identify patients who would benefit from expedited initiation of treatment.

Sex differences in prognostic utility of peripheral eosinophil count in first-line immune checkpoint therapy against metastatic NSCLC.

9067 Background: To date, few studies have associated elevated Absolute Eosinophil Count (AEC) with improved outcome to a single agent immune checkpoint inhibitor (ICI) as first or subsequent line of therapy in patients with NSCLC. Here, we investigated prognostic utility of AEC and the sex difference in patients undergoing standard-of-care first-line ICI with or without chemotherapy for metastatic NSCLC. Methods: This was a retrospective cohort study of 310 patients with Stage IV NSCLC treated with first-line ICI-based therapies (alone or in combination with chemotherapy) under IRB approved protocol 2021C0069. Demographic data are summarized in the table. Peripheral AEC measured by cells/microL was collected within 1 week before the start of therapy. Eosinophil count was evaluated in males and females by both descriptive statistics and Chi-squared test as a continuous and categorical variable, respectively. High level of baseline AEC was defined as 75th percentile (270 cells/microL). Overall Survival (OS) was plotted using the Kaplan-Meier method and p-values from log-rank test were reported. PD‐L1 was assessed by tumor proportion score (TPS) and classified into &lt; 1%, 1 to 49% and ≥ 50%. Results: 14% male vs 6% female patients were found to have peripheral eosinophilia (AEC ≥ 500) at the start of immunotherapy, p = 0.02. Patients with lower AEC had a median OS of 18.6 months vs 29.3 months in those with higher AEC ( p = 0.02, HR: 1.465, 95% Cl: 1.073-2.001). Patients with higher baseline AEC showed a sex difference, with median OS of 23.9 months in males vs NR median OS in females with over 60% survival at the time of last follow up ( p = 0.04, HR: 1.934, 95% Cl: 1.040-3.597). This difference was seen with ICI monotherapy ( p = 0.02, HR: 2.630, 95% Cl: 1.192-5.805), but not ICI with chemotherapy ( p = 0.83, HR: 1.116, 95% Cl: 0.4054-3.070). Higher AEC was associated with TPS ≥ 50% in both males and females ( p = 0.004 and 0.001, respectively), though no significant sex difference was observed. Conclusions: Our data highlight critical sex differences in interpretation of baseline AEC in patients on ICI therapy for metastatic NSCLC. While males have a higher frequency of peripheral eosinophilia, higher AEC correlates to improved OS predominantly in females. Further, this female-biased outcome is seen only with ICI monotherapy, even though higher AEC is associated with high PD-L1 expression in both sexes. Future studies are indicated to assess the longitudinal trend in eosinophil count as well as their active versus passive role in anti-tumor immunity and toxicity in the presence or absence of chemotherapy. [Table: see text]

Association of neutrophil to eosinophil ratio (NER) with clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with first-line (1L) immune checkpoint inhibitors (ICI) –based regimens.

4557 Background: ICI-based regimens (ICI + ICI or ICI + VEGF targeted therapy [VEGF-TT]) represent current standard of care systemic therapies for the management of patients with mRCC. Robust biomarkers capable of predicting the therapeutic efficacy and safety of such regimens are still lacking. Eosinophils have been shown to play an important role in the response to immunotherapy. While recent investigations in RCC evaluated NER as a biomarker of poor response to immunotherapy, they did not fully account for the impact of different lines of therapy and the therapeutic classes of ICI-based regimens. We aimed to comprehensively evaluate the association of NER with clinical outcomes in patients with mRCC treated with 1L ICI regimens. Methods: We retrospectively reviewed data from patients with mRCC treated with first line ICI-based regimens (dual ICI or ICI + VEGF-TT) at Dana-Farber Cancer Institute. Clinicodemographic information was collected, including tumor histology, ECOG performance status, IMDC risk score. We examined NER at baseline and at 6, 12, and 24 weeks while patients were still receiving treatment. The primary endpoint was overall survival (OS). Time to treatment failure (TTF) was a secondary endpoint. The association of NER with OS and TTF was evaluated using Cox regression models, adjusted for age, gender, BMI, histology, IMDC risk score and autoimmune disease. Results: Overall, 156 patients were included in the current analysis, with a median age of 61 years (IQR: 54-67). 60 patients received dual ICI therapy, while 96 were treated with ICI + VEGF-TT combinations. In the ICI+ICI group, a higher NER at baseline, 6 and 12 weeks was associated with worse OS. In the ICI + VEGF group, a higher NER only at 6 weeks appeared to be associated with worse OS. No association between NER and TTF was found. Conclusions: To our knowledge, this is the first study to investigate, across therapeutic classes, the association of NER with clinical outcomes in patients with mRCC treated with 1L ICI-based regimens. Higher NER was linked to poor survival outcomes, especially in patients receiving dual ICI therapy. Future translational studies are needed to clarify these findings. [Table: see text]

Multiple antigen stimulating cellular therapy (MASCT)-I for metastatic urothelial carcinoma (mUC): A multicenter, phase I study (MASCT-I-1001).

e16572 Background: Immune checkpoint inhibitors (ICIs) showed unsatisfactory efficacy in mUC. This study aimed to evaluate the role of MASCT-I alone, or plus camrelizumab or chemotherapy in patients (pts) with mUC. Methods: Eligible pts were enrolled in five groups (G): MASCT-I alone as salvage treatment in pts who failed standard treatment (G1), or as maintenance therapy following first-line platinum based-chemotherapy (G2); MASCT-I plus camrelizumab in pts who had progressed after first-line chemotherapy (G3) or ICI (G4), and MASCT-I plus platinum-based chemotherapy as first-line treatment (G5). Pts in G2 were allowed to be enrolled in G3 when disease progressed. The primary endpoint was safety. The secondary endpoints included progression-free survival (PFS) and overall survival (OS). Dynamic biomarker analysis of specific immune responses against 15 antigens was performed by enzyme-linked immunospot assays (ELISPOT) in peripheral blood mononuclear cells from pts. Results: Thirty-nine pts were included from February 16th, 2017 to March 3rd, 2022, with two, 18, nine, four and six pts in G1, 2, 3, 4 and 5, respectively. The pts were 37-72 years old, and 69.2% were male. The main MASCT-I-related adverse events (AEs) included grade 1/2 flushing, pruritus, rash, muscle cramp, fever, and arthralgia. Two pts experienced serious AEs related to both MASCT-I and camrelizumab, including grade 3 rash, adrenocortical insufficiency, and pleural effusion in one pt, and grade 3 elevated transaminases in another. No MASCT-I-related death occurred. No new safety signal related to chemotherapy or camrelizumab was reported. Thirty-six out of 39 pts had at least one response evaluation, with one complete response, six partial response and 13 stable diseases. The median PFS and OS for all pts was 2.3 months and 15.5 months, respectively. The median PFS and OS for pts in G2 was 3.0 months and 39.3 months, respectively. Pts in G2 presented significantly superior OS compared with pts in other groups ( P&lt; 0.001). In nine pts enrolled in G3 after progression in G2, the OS was significantly longer than other nine pts in G3 (median OS: not reached vs 15.4 months, hazard ratio [HR] = 0.14, 95% confidence interval [CI]: 0.03-0.61, P= 0.034). Among 24 pts with available ELISPOT analysis, six were defined as responders, which showed a significant prolonged PFS and OS compared with the non-responders (median PFS: 10.1 vs 4.5 months, HR = 0.33, 95% CI: 0.13-0.81, P&lt; 0.005; median OS: not reached vs 13.5 months, HR = 0.19, 95% CI: 0.05-0.70, P&lt; 0.005). Conclusions: Both MASCT-I alone or combined with immunotherapy or chemotherapy showed manageable safety profiles. Maintenance of MASCT-I after first-line chemotherapy presented inspiring survival benefit. Synergistic effects between MASCT-I and ICIs may exist. Potential candidates for MASCT-I treatment may be identified by ELISPOT analysis. Clinical trial information: NCT03034304 .

Real-world outcomes of first-line immune checkpoint inhibitors with or without chemotherapy in KRAS G12C altered NSCLC according to PD-L1 status.

9136 Background: There is a considerable debate whether treatment approaches should be tailored in advanced KRAS G12C-mutated NSCLC. Increasing evidence suggests that KRAS G12C-mutated NSCLC is associated with genomic heterogeneity that may impact clinical outcomes. Herein, we report a multimodal, real world outcomes analysis of 1L patients with advanced KRAS G12C-mutated NSCLC stratified by treatment type and PD-L1 status. Methods: Deidentified multimodal real-world data (RWD) of 1576 advanced, 1L NSCLC patients across the US were retrospectively analyzed from the Tempus database. Selection criteria included: Tempus xT targeted NGS, known PD-L1 status, absence of EGFR, ALK and ROS1 mutations, and treatment with chemotherapy (CT) + pembrolizumab (P), or P only. Patients were stratified by the presence or absence (wt) of KRAS G12C alterations. Median OS (mOS) was estimated using Kaplan-Meier methods. Subgroup analyses were performed using Cox model stratified by KRAS G12C status, PD-L1 status, and pathogenic alterations of STK11 and KEAP1. Results: In this study, two cohorts were assessed, KRAS G12C (n = 201) and KRAS G12C wt (n = 1375). Characteristics and demographics were balanced between both cohorts. Among TPS &lt; 50 patients treated with CT + P, KRAS G12C (n = 109, 54%) had a mOS of 11.64 months (m) versus 16.81m (HR = 1.32, p = 0.06) for KRAS G12C wt (n = 864, 62.8%). Among TPS &lt; 1 patients treated with CT + P, KRAS G12C (n = 46, 22%) had a mOS of 11.18 m versus 16.44 m (HR = 1.67, p = 0.01) for KRAS G12C wt (n = 489, 35%). Among TPS ≥50 patients treated with P only, KRAS G12C (n = 45, 22.3%) had a mOS of 30.03m compared to 25.03m (HR = 0.94, p = 0.83) in KRAS G12Cwt (n = 236,17.1%). TPS &lt; 50 subgroup was enriched for select co-mutations with KRAS G12C ( STK11, 24.5%; KEAP1, 10.7%) vs. TPS ≥50 ( STK11, 3.8%; KEAP1, 5.1%). When evaluating the impact of co-mutations in the KRAS G12C with TPS &lt; 50, STK11 (n = 30) mOS was 10.59m (HR = 1.01, p = 0.81) and KEAP1 (n = 13) mOS was 7.63m (HR = 2.14, p = 0.03). Conclusions: This largest RWD analysis to date demonstrates that 1L KRAS G12C NSCLC patients with TPS &lt; 1% and &lt; 50% receiving standard CT + P have the shortest survival among all evaluated sub-groups. Novel KRAS G12C targeted combination therapies in development for this patient population may offer the promise of better outcomes. [Table: see text]

PLUME: A single-arm phase II trial evaluating the combination of pembrolizumab and lenvatinib in metastatic uveal melanoma (mUM) patients (pts) previously treated or not with tebentafusp.

TPS9613 Background: Up to 50% of pts with uveal melanoma (UM) develop metastases, mainly hepatic, with poor overall survival and limited treatment options as response rate to first-line immune checkpoint inhibitors (ICI) is low in mUM pts. Tebentafusp, a bispecific T-cell engager, was recently approved in this setting but only in HLA A*02-01+ mUM patients. Lenvatinib is a tyrosine kinase inhibitor targeting multiple growth factor receptors including vascular endothelial growth factor receptors (VEGFRs), fibroblast growth factor receptors (FGFRs) and colony-stimulating factor receptor (CSF1-R), which are key pathways in UM. Lenvatinib showed an immune-modulating effect in preclinical models. The combination demonstrated synergic clinical anti-tumor activity in various tumor types including microsatellite-stable endometrial cancers, kidney cancers and ICI-resistant skin melanomas. We hypothesize that combining pembrolizumab with lenvatinib in mUM may lead to an improved immune response in mUM patients. Methods: Fifty-four, ICI-naïve, metastatic UM pts will be enrolled in this monocentric, single-arm phase II trial at Institut Curie, Paris, France. Because previous exposure to tebentafusp might increase the activity of subsequent ICI, the combination will be assessed in two independent cohorts: cohort 1 with HLA A*02-01neg, tebentafusp-naive patients (22 assessable patients), and cohort 2 with HLA A*02-01pos pts previously treated with tebentafusp (28 assessable patients). Up to 54 patients may be included according to an 8% drop-out rate. Each participant will receive pembrolizumab (200 mg Q3W, maximum of 35 cycles) plus lenvatinib (starting at 20mg QD) until reaching a discontinuation criterion. Liver MRI and chest-abdomen-pelvis CT will be performed every 9 weeks until progressive disease. Primary objective is to evaluate the progression-free survival (PFS) after nine cycles of treatment (27 weeks) as assessed by the investigator using the RECIST v1.1. Secondary objectives include PFS according to immune RECIST (iRECIST), overall survival, overall response rate, safety and tolerability, quality of life. Inclusion period started mid-July 2022 for two years. To date, twenty-four (21 in cohort 1, 3 in cohort 2) of planned 54 pts have been enrolled in six months. Biospecimens (longitudinal blood samples and tumor tissue at inclusion) will be collected during the study to allow biomarker research. Clinical trial information: NCT05282901 .

Combination of AFP vaccine and immune checkpoint inhibitors slows hepatocellular carcinoma progression in preclinical models.

Many patients with hepatocellular carcinoma (HCC) do not respond to the first-line immune checkpoint inhibitor treatment. Immunization with effective cancer vaccines is an attractive alternative approach to immunotherapy. However, its efficacy remains insufficiently evaluated in preclinical studies. Here, we investigated HCC-associated self/tumor antigen, α-fetoprotein-based (AFP-based) vaccine immunization for treating AFP (+) HCC mouse models. We found that AFP immunization effectively induced AFP-specific CD8+ T cells in vivo. However, these CD8+ T cells expressed exhaustion markers, including PD1, LAG3, and Tim3. Furthermore, the AFP vaccine effectively prevented c-MYC/Mcl1 HCC initiation when administered before tumor formation, while it was ineffective against full-blown c-MYC/Mcl1 tumors. Similarly, anti-PD1 and anti-PD-L1 monotherapy showed no efficacy in this murine HCC model. In striking contrast, AFP immunization combined with anti-PD-L1 treatment triggered significant inhibition of HCC progression in most liver tumor nodules, while in combination with anti-PD1, it induced slower tumor progression. Mechanistically, we demonstrated that HCC-intrinsic PD-L1 expression was the primary target of anti-PD-L1 in this combination therapy. Notably, the combination therapy had a similar therapeutic effect in the cMet/β-catenin mouse HCC model. These findings suggest that combining the AFP vaccine and immune checkpoint inhibitors may be effective for AFP (+) HCC treatment.

Five-year survival outcomes in patients with melanoma with complete response to immunotherapy who discontinue therapy.

e21503 Background: Immune checkpoint inhibitor (ICI) therapy for advanced melanoma in the first-line setting often results in durable responses and prolonged overall survival (OS) after achieving a complete response (CR). While generally well-tolerated, there are financial toxicities and treatment related adverse events (TRAEs) associated with ICI use. There are limited data to inform the optimal duration of therapy after CR, and how specific patient factors may lead to variable OS in patients (pts) with CR. Methods: Pts with locally advanced stage III or stage IV melanoma who started first-line ICI therapy with pembrolizumab, nivolumab, or ipilimumab/nivolumab (ipi/nivo) and achieved CR were identified at a single institution under an Institutional Review Board approved protocol. Pts were only included in the sample if they had initiated treatment by 2013 and discontinued therapy by February of 2021 and had documented follow-up at least 1 year after discontinuing ICI therapy. Recurrence rates were determined by the presence of any recurrence after CR. Pts were analyzed by baseline stage (III vs IV), BRAF status, use of steroids for TRAEs, time from treatment start to CR, and total duration of therapy. OS was determined by time from treatment start to death or date of last follow-up. Results: 78 Pts with CRs from ICI therapy who discontinued treatment were identified at the University of Pennsylvania. Median follow-up time was 63 months from ICI treatment start. Median age at treatment start was 65 years (range 33-94). 51 Pts (68%) had an ECOG performance status (PS) of 0 vs 24 (32%) with ECOG PS of 1-2. 21 Pts (27%) had locally advanced stage III and 57 (73%) had stage IV disease. Of stage IV pts, 8 were M1a, 16 M1b, 22 M1c, and 11 M1d. 61 (78%) pts were treated with pembrolizumab, 5 (6%) nivolumab, 12 (15%) ipi/nivo. 34 pts (44%) were treated with steroids for TRAEs. Of the 78 total pts, 13 (16.7%) developed a recurrence after stopping treatment. The median time to recurrence was 57 months (range 9-110). Melanoma specific survival was 96%. Of the pts with recurrence, 3 died of melanoma, 9 are disease free after additional local and/or systemic treatment and one patient is alive with disease. There was no significant difference ( p &lt; 0.05) in OS based on baseline stage, BRAF status, or use of steroids for TRAEs. Pts were treated for a median of 6 months (range 1 day to 24 months). Conclusions: With over 5 years median follow-up time, the majority of pts with advanced melanoma who attain a CR from first-line ICI therapy remain disease free after treatment discontinuation. Patient factors including stage at treatment initiation, BRAF status, and steroid usage during treatment were not associated with significant variation in OS in this cohort. Most pts with recurrences remain disease free after additional local and/or systemic treatment. Few melanoma specific deaths occurred in pts with a CR to ICI who discontinued treatment.