Addition Of Immune Checkpoint Inhibitors Research Articles

Comparative efficacy of immune checkpoint inhibitors combined with chemotherapy in patients with advanced driver-gene negative non-small cell lung cancer: A systematic review and network meta-analysis

ObjectiveTo evaluate the efficacy of different combinations of immune checkpoint inhibitors (ICIs) and chemotherapy (CT) in the treatment of advanced non-small cell lung cancer (NSCLC). MethodsWe obtained relevant randomized controlled trials (RCTs) from databases such as PubMed, Embase, Web of Science, and The Cochrane Library up to May 31, 2023. The analysis of clinical prognostic factors was performed using R 4.2.3 and STATA 15.0. The main outcomes measured were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included the objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events of grade 3–5 severity (Grade ≥3 TRAE). ResultsA total of 17 randomized controlled trials (RCTs) were conducted between 2012 and 2023, involving 7792 patients. These trials evaluated 11 different treatment methods. The results of these trials showed that in terms of overall survival (OS) and progression-free survival (PFS), the combination of tislelizumab with chemotherapy and the combination of camrelizumab with chemotherapy were particularly effective. Moreover, when compared with other combination therapies, pembrolizumab combined with chemotherapy showed superiority in terms of disease control rate (DCR) and objective response rate (ORR). Subgroup analyses further demonstrated that the addition of immune checkpoint inhibitors (ICIs) to chemotherapy significantly improved PFS and OS in patients without liver metastasis and in those with brain metastasis. Additionally, carboplatin-based combination therapy was found to confer favorable survival benefits in terms of PFS, while cisplatin-based combination therapy showed the most favorable outcomes in terms of OS. The results of subgroup analyses for overall survival (OS) showed that the combination of immunotherapy and chemotherapy yielded positive outcomes in specific subgroups. These subgroups were characterized by PD-L1 Tumor Proportion Score (TPS) of 50 % or higher, usage of anti-PD-1 medications, age below 65, male gender, smoking history, and non-squamous cell carcinoma histology. Superior effectiveness was demonstrated only in extending the progression-free survival (PFS) of female patients and patients with squamous carcinoma. Meanwhile, other patient cohorts did not show the same level of improvement. ConclusionsTislelizumab, camrelizumab or pembrolizumab combined with chemotherapy may be the optimal first-line treatment strategies for NSCLC.

Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200mg every 3 weeks) for three cycles plus FLOT (50mg/m 2 docetaxel, 80mg/m 2 oxaliplatin, 200mg/m 2 calcium levofolinate, 2600mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

Abstract 5080: Antibody drug conjugate trastuzumab deruxtecan suppresses leptomeningeal brain metastasis cells and is potentiated by addition of immune check point inhibitor

Abstract Leptomeningeal disease (LMD) is defined by dissemination of metastatic cancer cells into the subarachnoid space with subsequent involvement of the cerebrospinal fluid and leptomeninges. LMD is an aggressive, late-stage development of cancer, which is increasing in prevalence as improved treatments for systemic malignancies are discovered. It leads to significant neurological morbidity and mortality, and outcomes remain poor despite improving cancer treatment strategies. There is a large population of patients with human epidermal growth factor receptor 2 (HER2) expressing cancers, such as breast and lung cancers, who suffer from leptomeningeal metastasis. There has been evolving research looking at antibody drug conjugates for treatment of these primary pathologies, such as Trastuzumab Deruxtecan (TDxd), which shows improved progression free survival and overall survival in those with HER2 expressing primary cancers, as well as in intraparenchymal brain metastasis. However, as of yet there has been no study of its utility in LMD. Additionally, use of immune check point inhibitors (ICI) for treatment of LMD has been studied, showing some efficacy, but less robust response than that in intraparenchymal brain metastasis. Given the significant population of patients who continue to be affected by leptomeningeal metastasis, there is significant need for an improved treatment regimen. We hypothesize that TDxd will have a killing effect on HER2 expressing LMD cells, which can be further potentiated by the addition of ICIs. To test this hypothesis, we developed breast and lung cancer cell lines (SKBrM-LMD, and H2030BrM-LMD) that express HER2 and preferentially metastasize to leptomeningeal space. These cell lines were also labeled with luciferase. We then treated these cell lines with TDxd and found that TDxd had significant growth inhibitory effect on these cells in vitro when compared to the control. Furthermore, we educated human T Cells against the SkBrM-LMD cells and treated these cells with the aforementioned T cells plus the ICI Anti-PD1. Our results showed that ICI had significant killing effect when compared to the control. We have also created an in vivo LMD model by performing intraventricular injection of HER2 expressing tumor cells into a mouse model, which can be used for testing the efficacy of TDxd and ICI by intrathecal injection. In conclusion, our results indicate that TDxd and ICI have significant killing activity against HER2 expressing LMD cells, and therefore intrathecal administration of these drugs is a promising treatment modality that will be demonstrated using a mouse LMD model. Citation Format: Eleanor C. Smith, Shih-Ying Wu, Ravindra P. Deshpande, Abhishek Tyagi, Kounosuke Watabe. Antibody drug conjugate trastuzumab deruxtecan suppresses leptomeningeal brain metastasis cells and is potentiated by addition of immune check point inhibitor [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 5080.

Abstract 1173: T cell receptor diversity in buffy coat samples from subsets of breast and ovarian cancer patients

Abstract Background: Immunotherapy, mainly by the use of immune checkpoint inhibitors (ICI), has been established as a standard option for both, solid tumors and hematological malignancies. Unfortunately, this success has only been replicated in a subset of patients (pts) with gynecological cancers. In ovarian cancer (OC), response rates to ICI monotherapy were low and in breast cancer (BC), only the subgroup of triple-negative BC (TNBC) pts showed an improved outcome by the addition of ICI. One reason for limited success of immunotherapy might be an impaired immune system. In this regard, monitoring the T cell receptor (TCR) repertoire could provide key insights into adaptive immune responses to ultimately understand disease initiation, progression and treatment response. Here we elucidated TCR alpha, beta, gamma and delta in buffy coats of pts with non-metastatic OC as well as non-metastatic and metastatic TNBC and compared the results with healthy donors (HDs). Methods: RNA was isolated from buffy coat samples of 20 HDs, 10 treatment-naïve primary OC pts, 14 treatment-naïve, non-metastatic TNBC pts (participating in the phase II neomono trial) and 19 pts with metastatic TNBC by a modified QIAamp RNA Blood Mini protocol. A survey of the TCR diversity and mapping of common and unique TCRs was done using the QIAseq Targeted RNA Panel Human TCR panel for all known T-cell receptors (alpha, beta, gamma, delta). Results: Regardless of the cancer entity, a significant reduction in TCR diversity was observed compared to HDs with the greatest differences observed in the delta receptors. When OC samples were compared with HDs, the difference in diversity was highly significant for all TCR subtypes (TCRalpha: p=0.013; TCRbeta: p=0.008; TCRgamma: 0.008; TCRdelta: 0.006). Similar results were obtained for non-metastatic TNBC (TCRalpha: p=0.0002; TCRbeta: p=0.0001; TCRgamma: p=0.002; TCRdelta: p=0.002) as well as metastatic TNBC patients (TCRalpha: p=0.001; TCRbeta: p=0.001; TCRgamma: p=0.005; TCRdelta: p=0.003) when their TCR diversity was compared to HDs. Interestingly, no significant differences in diversity were obtained when treatment-naïve non-metastatic TNBC pts were compared with heavily pretreated metastatic TNBC pts. The lowest diversity was found in BC pts compared to the OC pts. Conclusion: We have initiated a survey of the TCR diversity in TNBC and OC patients. Further evaluations will include the correlation of these findings with clinical characteristics and outcome. Whether the reduced TCR diversity represents T cell exhaustion or T cell specialization cannot yet be deduced from the results. Nevertheless, the addition of a TCR diversity score could provide an additional metric which may help provide patient guidance when integrated into a multi-modal molecular test. Citation Format: Corinna Keup, Cornelia Kolberg-Liedtke, Song Tian, Samuel J. Rulli, Siegfried Hauch, Paul Buderath, Oliver Hoffmann, Rainer Kimmig, Sabine Kasimir-Bauer. T cell receptor diversity in buffy coat samples from subsets of breast and ovarian cancer patients [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 1173.

Treatment-related adverse events of combination chemoimmunotherapy versus chemotherapy alone in first-line treatment for non-small cell lung cancer: a systematic review and meta-analysis of randomized clinical trials.

Numerous meta-analyses have examined immunotherapy-induced adverse events (AEs) in non-small cell lung cancer (NSCLC). However, there is limited research comparing AEs from combination chemoimmunotherapy versus chemotherapy alone in the first-line NSCLC treatment, particularly regarding specific toxic symptoms and hematological toxicities associated with the addition of immune checkpoint inhibitors (ICIs). We conducted a meta-analysis of randomized clinical trials (RCTs) comparing ICIs + non-ICIs versus non-ICIs alone as first-line therapy in NSCLC, sourced from PubMed and Scopus databases. Our objective was to assess treatment-related AEs in both regimens, focusing on identifying the more prevalent toxic symptoms and hematological toxicities with ICI treatment. We calculated the relative risks (RRs) and 95% confidence intervals (CIs), and estimated the pooled RRs and 95% CIs using common- or random-effects models. Our analysis included 10 trials with 6,008 patients. Combination chemoimmunotherapy significantly increased the risk of grade 3 or higher treatment-related AEs, treatment discontinuation, and deaths due to treatment-related AEs. Moreover, patients receiving combination chemoimmunotherapy had a significantly higher risk of certain toxic symptoms (all-grade: vomiting, diarrhea, and constipation; high-grade: fatigue and diarrhea) and pneumonitis (both all-grade and high-grade). These findings offer crucial insights into the toxicity profile of combination chemoimmunotherapy, serving as a valuable resource for clinicians managing lung cancer care.

Relationship between patterns of immunohistochemical conventional neuroendocrine markers and efficacy of immune check point inhibitors in patients with extensive disease small cell lung cancer.

Which patients benefit from the addition of immune checkpoint inhibitors (ICIs) to chemotherapy for small cell lung cancer (SCLC) remains unclear. There have been few reports on the efficacy of ICIs based on conventional immunohistochemical neuroendocrine (NE) markers (synaptophysin, chromogranin A, and neural cell adhesion molecule [NCAM]). In the present study, we aimed to analyze the relationship between the expression of immunohistochemical NE markers and the efficacy of ICIs in patients with extensive disease (ED)-SCLC, to assess whether conventional NE markers are predictive of ICIs. Patients with untreated ED-SCLC who received first-line therapy at the Shizuoka Cancer Center between November 2002 and July 2021 were retrospectively reviewed. We evaluated the efficacy of first-line chemotherapy according to the expression status of each immunohistochemical NE marker in patients treated with ICI plus chemotherapy (ICI-chemo group) and with chemotherapy alone (chemo group). A total of 227 patients were included in the ICI-chemo and chemo groups, respectively. The progression-free survival (PFS) tended to be better in patients in the ICI-chemo group than those treated with chemotherapy alone in patients with NE marker-positive SCLC. In particular, it was statistically significant in patients with chromogranin A-positive SCLC (p = 0.036). In patients with NE marker-negative SCLC, no significant differences were observed in PFS between the two groups. There were no significant differences in overall survival (OS), regardless of the expression of any conventional NE marker. Our study suggests that the efficacy of ICIs in addition to chemotherapy may be poor in patients with NE marker-negative SCLC.

Current and Emerging Therapeutic Targets for the Treatment of Cholangiocarcinoma: An Updated Review.

Cholangiocarcinoma is a malignancy of the bile ducts that is often associated with late diagnosis, poor overall survival, and limited treatment options. The standard of care therapy for cholangiocarcinoma has been cytotoxic chemotherapy with modest improvements in overall survival with the addition of immune checkpoint inhibitors. The discovery of actionable mutations has led to the advent of targeted therapies against FGFR and IDH-1, which has expanded the treatment landscape for this patient population. Significant efforts have been made in the pre-clinical space to explore novel immunotherapeutic approaches, as well as antibody-drug conjugates. This review provides an overview of the current landscape of treatment options, as well as promising future therapeutic targets.

Tumour microenvironment influences response to treatment in oesophageal adenocarcinoma.

The poor treatment response of oesophageal adenocarcinoma (OAC) leads to low survival rates. Its increasing incidence makes finding more effective treatment a priority. Recent treatment improvements can be attributed to the inclusion of the tumour microenvironment (TME) and immune infiltrates in treatment decisions. OAC TME is largely immunosuppressed and reflects treatment resistance as patients with inflamed TME have better outcomes. Priming the tumour with the appropriate neoadjuvant chemoradiotherapy treatment could lead to higher immune infiltrations and higher expression of immune checkpoints, such as PD-1/PDL-1, CTLA4 or emerging new targets: LAG-3, TIM-3, TIGIT or ICOS. Multiple trials support the addition of immune checkpoint inhibitors to the current standard of care. However, results vary, supporting the need for better response biomarkers based on TME composition. This review explores what is known about OAC TME, the clinical significance of the various cell populations infiltrating it and the emerging therapeutical combination with a focus on immune checkpoints inhibitors.

Addition of immune checkpoint inhibitors to chemotherapy versus chemotherapy alone in patients with triple-negative breast cancer: A systematic review and meta-analysis.

Triple-negative breast cancer (TNBC) is a relatively common malignant tumor with high mortality rates. There are limited treatment options and current therapy regimens often fall short of providing positive outcomes. The development of immune checkpoint inhibitors (ICIs) have provided a vital treatment option although efficacy has varied. Here, we review patient response to current TNBC treatment with and without the addition of ICIs. A systematic search of PubMed, Cochrane, and EMBASE library databases was done to search eligible studies published from their inception through April 3, 2022. The primary outcome indicators used were progression-free survival (PFS), overall survival (OS), pathological complete response rate (pCR) and objective remission rate (ORR), while adverse events (AEs) were also analyzed. Publication bias and sensitivity analyses and were performed to evaluate the quality of assessment. Overall, the meta-analysis looked at seven randomized controlled trials (RCTs) that included 4631 patients with TNBC. Results showed an improvement in PFS for patients receiving ICI in addition to chemotherapy (CT) in both the intent-to-treat (ITT) population and PD-L1 positive patients. Increased pCR rates were observed in all patients irrespective of PD-L1 status as well as increased ORR in the ITT which was more notable in PD-L1 positive subjects. While significant improvement in OS was observed only in PD-L1 positive individuals, the use of ICIs plus CT resulted in severe adverse reactions, specifically immune-related. This study supports the increased efficacy of ICIs in combination with CT compared to CT alone in patients with TNBC, with the most notable benefit observed in PD-L1 positive patients. However, combination therapy increases the risk of adverse reactions which warrants further investigation.

Engraftment Syndrome Incidence after Immune Checkpoint Inhibitor Therapy in Pts with Classical Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplantation: A Single Institutional Review

Introduction: After receiving frontline chemotherapy for classical Hodgkin lymphoma, up to 30% of patients (pts) relapse. Salvage chemotherapy and autologous stem cell transplantation (ASCT) are the standard of care. Immune Checkpoint inhibitors (ICIs) have become essential to salvage therapy with improved complete response (CR) rates. However, ICIs have been linked to an increased risk of engraftment syndrome (ES), reported in as many as 68-78% of cases (Moskowitz et al. 2021; Park et al. 2021), while others have reported lower rates 3-12% (Bryan et al. 2023; Mei et al. 2022). The variability is connected to the definition of ES. The more stringent Spitzers criteria require 3 major (non-infectious fever (NIF), skin rash, pulmonary edema, or hypoxia) or 2 major and 1 minor criteria within 96 hours of engraftment, while the more lenient Maiolino criteria require a NIF with skin rash, pulmonary infiltrates, or diarrhea. Early diagnosis of ES and early intervention with corticosteroids is important to minimize toxicity during the ASCT. Here, we evaluate ES incidence at our institution during ASCT with or without the inclusion of ICI during salvage therapy. Method: The institutional database was queried for pts with relapsed/refractory cHL who underwent ASCT between 2018 and 2023. ES is broadly defined as the presence of non-infectious fever with skin rash, diarrhea, or pulmonary infiltrates (Maiolino Criteria) or clinical suspicion requiring corticosteroids. Results: A total of 47 pts underwent ASCT during this period and were included in the final analysis. Twenty-nine pts received ICI during salvage therapy (72%). Regarding basic patient characteristics: the median age at ASCT was 31 [19-72], 27 pts were female (57.5%), 35 pts were white (74.5%), the most common subtype was nodular sclerosis (n=42; 89.4%), with 23 pts (50%) initially presenting with advanced-stage disease. The most common initial therapy was ABVD (n=42, 89.4%), with one patient being treated with an ICI-based therapy on clinical trial (SWOG 1826). Thirty pts (63.8%) had a CR after frontline treatment and 16 pts with primary refractory disease. For the CR pts, the median time to progression was 159 [13-3864] days. Thirty-five pts achieved a CR after salvage therapy (74.5%), 25 receiving ICI (71.4%), most commonly pembrolizumab. Regarding conditioning regimens, the most used and our institutional standard is total lymphoma irradiation (TLI) followed by high-dose chemotherapy (CCV) (n=34; 72.3%), which we have reported having high and durable response rates (10-yr PFS 68.5% and OS 68.0%). (Paudel et al. 2019) The median time to neutrophil engraftment is 10 days [7-30]. The rate of post-ASCT relapse was higher in the chemotherapy-only conditioning group (31%) compared to TLI-CCV (3.3%). All pts who received TLI-CCV are still alive, with two deaths in the chemotherapy only conditioning group (Total OS 95.7%). Out of 47 evaluable pts, no pts qualified with a diagnosis of ES using the stringent Spitzers criteria. However, 17 received corticosteroids using the broader diagnosis criteria for ES (36%). Looking specifically at pts who received ICI (n=29), 14 pts had ES (48.3%), while of the 18 pts who did not receive ICI, 3 had ES (16.7%). Of the pts who did develop ES (n=17), 16 pts received TLI-CCV (94%), the median time to onset was 9 [2-11] days, the median time to resolution was 6 [2-19] days, the median time to neutrophil engraftment was 10 [8-12] days. When evaluating pts who received TLI-CCV conditioning, 24 pts received ICI during treatment before ASCT, with 13 pts having ES (54.2%). By comparison, 3 (33%) of the 9 ICI-naïve pts who received TLI-CCV were diagnosed with ES. The incidence of ES with or without ICI exposure was not statistically significant (p = 0.2549). Overall, the median time to ES onset is 9 days, and the duration of 6 days. There was no recorded mortality from ES. Only 3 pts relapsed post-ASCT (8.8%), with two receiving ICIs. Even with the small number of pts in this retrospective study, there was an increase in ES incidence between the use of ICI during salvage therapy (p=0.0279). Conclusions: In this single-institution retrospective analysis, we found that the addition of ICI during salvage therapy increased the incidence of a broadly defined ES, with an increase in corticosteroid use. ES must be recognized early and treated with corticosteroids aggressively.

OGC O06 Long term outcomes of immune checkpoint inhibition in oesophageal cancer

Abstract Background Phase III studies have shown a survival benefit for the addition of immune checkpoint inhibitors (ICIs) to conventional chemotherapy for patients with gastro-oesophageal cancer. Large scale studies of chemo-immunotherapy prior to and after surgery are under way. We studied the clinical and biological effects of adding the PD-L1 inhibitor durvalumab (D) to peri-operative chemotherapy or chemoradiotherapy in a multi-centre phase II trial and used multiple phenotyping approaches to identify features associated with benefit. Methods Patients suitable for surgery were given D for 4 weeks, then one of Oxaliplatin and Capecitabine (CapOx), fluorouracil, leucovorin, oxaliplatin and taxotere (FLOT), or chemoradiotherapy (CXRT, CROSS regimen) were given with D before surgery, and D was continued for up to 12 further infusions postoperatively. Toxicity, response, and survival were recorded until death, for 3 years or until June 2022 when the study ended. Comparisons were made with propensity score matched patients treated over the same period in the one of the participating sites. Tumour phenotyping was with single cell and bulk sequencing approaches. Results 11 pts received D-CapOx, 9 D-FLOT and 15 D-CXRT. Treatment side effects were as expected. Only 2 out of 35 patients did not have surgery, due to progressive disease on D-CXRT. Two (5.7%) and 6 (17.1%) patients had complete or partial pre-op responses (RECIST) and 3 (8.6%) had progression prior to surgery. Tumour regression at surgery (Mandard 1-3) occurred in 24/33 pts. 2-year survival was 81.8%, 77.8% and 77.8% respectively in the 3 arms. After propensity score matching, there was a survival advantage after addition of ICI (p=0.047). In selected patients we also demonstrate molecular features associated with response. Conclusions Adding D to standard neo-adjuvant regimens for gastro-oesophageal cancer is well tolerated. Survival times and response rates exceeded those expected for the regimens used (2-year survivals with FLOT 68% and CROSS 67%) in this non-randomised multi-centre trial. There was a survival advantage from the addition of ICI when compared to a matched cohort of patients treated in one of the study centres over the same period. Specific pre-treatment tumour phenotypes were associated with durable cure.

Immune checkpoint inhibitors with chemotherapy for primary advanced mismatch repair-deficient endometrial cancer: A cost-effectiveness analysis

ObjectiveThe addition of immune checkpoint inhibitors (ICIs), pembrolizumab or dostarlimab, to paclitaxel and carboplatin (TC) has shown better response rates and survival outcomes for patients with primary advanced mismatch repair-deficient (MMRd) endometrial cancer (EC) in NRG-GY018 and RUBY, respectively. Nonetheless, the high cost of ICIs remains a major concern when implementing this strategy in the real world. This study aimed to determine the cost-effectiveness of pembrolizumab and dostarlimab with chemotherapy compared to TC for primary advanced MMRd EC. MethodsWe developed a Markov model including 6600 patients with primary advanced MMRd EC to simulate treatment outcomes. The initial decision points in the model were treatment with pembrolizumab with TC (PEM-TC), dostarlimab with TC (DOS-TC), and TC. Model probabilities, costs, and health utility values were derived with assumptions from published literature. Effectiveness was determined as average quality-adjusted life years (QALYs) gained. The primary outcome was the incremental cost-effectiveness ratio (ICER). ResultsTC was the least costly strategy, whereas PEM-TC was the most effective strategy for primary advanced MMRd EC. TC was cost-effective based on a willingness-to-pay (WTP) threshold of $100,000/QALY compared with PEM-TC (ICER, $377,718/QALY), and DOS-TC exhibited absolute dominance (ICER, $401,859/QALY). PEM-TC was cost-effective when the cost of pembrolizumab 200 mg was reduced to $4361 (61% reduction). PEM-TC was selected in 16.5% with a WTP threshold of $300,000/QALY, but in <1% with a WTP threshold range of $100,000-200,000/QALY. ConclusionPEM-TC can become cost-effective for primary advanced MMRd EC when the cost of pembrolizumab substantially decreases.

SWOG S1929: Phase II randomized study of maintenance atezolizumab (A) versus atezolizumab + talazoparib (AT) in patients with SLFN11 positive extensive stage small cell lung cancer (ES-SCLC).

8504 Background: In unselected patients (pts) with extensive-stage small cell lung cancer (ES-SCLC), the addition of immune checkpoint inhibitors (ICI) to chemotherapy resulted in a modest improvement in OS. In a retrospective analysis of a study with veliparib (PARP inhibitor [PARPi]) and temozolomide in patients with SCLC, Schlafen-11 (SLFN11) predicted PFS and OS benefit for the addition of PARPi. We evaluated whether the addition of PARPi (talazoparib) to standard-of-care maintenance ICI (atezolizumab) following frontline chemoimmunotherapy improved outcomes in pts with SLFN11-positive ES-SCLC. Methods: Participants with ES-SCLC expressing SLFN11 (H-score ≥ 1, evaluated centrally at MDACC) were randomized to maintenance atezolizumab (A) versus atezolizumab plus talazoparib (AT) following frontline chemotherapy and A. Randomization was stratified by Zebrod PS (0-1 vs 2) and use of consolidation thoracic radiation. The primary endpoint was PFS, and secondary endpoints included ORR, OS, and toxicity. The primary analysis was done using a 1-sided 10% level stratified log-rank test. Target sample size was 94 pts. Results: From June 2020 to December 2022, 309 pts were screened, of which 204 of 259 (79%) with evaluable tissue were SLFN11 positive, and 106 were randomized (52 A, 54 AT). Median follow up time is 5 months. Median age was 67 (45-84); 51 (48%) were females; 94 (89%) were white,102 (96%) were PS 0-1, and 26 (25%) had radiation prior to randomization. With 80 PFS events reported, PFS was significantly improved with AT (hazard ratio [80% CI]: 0.70 [0.52-0.94]; p = 0.056). Median PFS was 2.8 months (80% CI 2.0-2.9) for A and 4.2 months (80% CI 2.8-4.7) for AT. OS was not different (hazard ratio [80% CI]: 1.17 [0.80-1.71]; p = 0.30). Median OS was 8.5 months (80 % CI 7.4-12.7) for A and 9.4 months (80% CI 8.1-14.2) for AT. ORR was 16% (5/32, 80% CI 8-27%) for A and 12% (4/34, 80% CI 5-22%) for AT. Grade 3 or greater treatment related non-hematological adverse events (AEs) occurred in 13% pts in A and 15% in AT. Hematological AEs occurred 4% in A compared to 50% pts in AT (Expected for T) (p &lt; 0.001). There were no treatment related grade 5 events. One participant on AT experienced grade 3 febrile neutropenia. The majority of grade 3 AEs were due to anemia (2% in A and 37% in AT). Only three pts discontinued treatment due to toxicity (2 in A and 1 in AT). Conclusions: This study met its primary endpoint demonstrating that maintenance AT improved PFS in SLFN11-selected patients with ES-SCLC. Hematologic toxicity was increased with AT as expected, with majority being grade 3 anemia. This study demonstrates the feasibility of conducting biomarker selected trials in SCLC, paving the way for future evaluation of novel therapies in selected SCLC populations. Clinical trial information: NCT04334941 .

Neoadjuvant immunotherapy in hepatocellular carcinoma: A systematic review and meta-analysis.

e16232 Background: The addition of immunotherapy in neoadjuvant hepatocellular carcinoma (HCC) has been studied recently in early phase clinical trials due to high rate of recurrence after surgery. We aim to systematically review the evidence of efficacy and safety of neoadjuvant immunotherapy treatment. Methods: We carried out a systematic search on MEDLINE, Cochrane, and ASCO meetings library. Screening was done to include clinical trials with HCC patients who underwent any combination of neoadjuvant immune checkpoint inhibitors (ICIs). Quality assessment was performed using methodological index for non-randomized studies (MINORS) tool. The primary efficacy outcomes evaluated included complete pathological response (pCR), major pathological response (MPR), 1 year recurrence free survival (RFS) and overall response rate (ORR). Treatment related adverse events (TRAE) were assessed as a safety outcome. Predefined subgroup analysis was performed based on studies including of tyrosine kinase inhibitors (TKIs) in regimen. Data was analyzed using R version 4.2.1. Results: 5 phase I/II clinical trials were included consisting of 96 patients. Trials administered neoadjuvant immunotherapy agents nivolumab (with TKI cabozantinib) (N = 1), camrelizumab (with TKI apatinib) (N = 1), cemiplimab (N = 1) and nivolumab plus ipilimumab (N = 2). 78(81.2%) of patients were males. 56(59.3%) of patients had viral etiology. 14(14.5%) patients had surgeries delayed or cancelled due to any cause per trial protocols. Meta-analysis of 96 patients from 5 trials showed a pooled pCR rate of 14.49% (95% CI: 6.82 to 23.93%) with low heterogeneity (I2 = 0%, p value 0.55). Pooling the MPR resulted in an estimate of 35.30% (95% CI: 18.80% to 53.57%) with significant heterogeneity (I2 = 58.8%, p value 0.04). Three trials with total 45 patients reported a 12-month RFS rate of 51.08% (95% CI: 40.59 to 70.67%) with significant heterogeneity (I2 = 84.2%, p value 0.002). The overall response rate was 13.7% (95% CI: 6.9 to 22.1%) (I2 =0%, p =0.8). Overall rate of TRAE of any grade was 73.8% (95% CI: 63.1 to 82.5%) (I2 = 83.4%, p &lt;0.001) among all trials and grade 3 adverse events was 21.21% (95% CI: 11.4 to 32.7%) (I2 = 33.8%, p = 0.159). 17(17.8%) patients had elevation in liver enzymes. On subgroup analyses, no difference in pathological outcomes, ORR and grade 3 adverse events was observed with addition of TKIs. Exploratory analysis showed no difference in pCR rates with single ICI vs combination with ipilimumab. Conclusions: The addition of ICIs in neoadjuvant settings appears to be a safe and feasible option. The addition of TKIs to neoadjuvant ICIs does not appear to affect pathological and safety outcomes. Further studies are needed to identify ICI based regimens to improve pCR rates and validate pathological outcomes in HCC after correlating with recurrence and survival.

Ramucirumab, avelumab and paclitaxel (RAP) as second line treatment in esophagogastric adenocarcinoma: Final results of the phase 2 RAP trial (AIO-STO-0218).

4032 Background: The addition of immune checkpoint inhibitors to chemotherapy has improved outcomes in patients (pts) with metastatic esophagogastric adenocarcinoma (EGA), but treatment combinations and optimal pt selection need to be established. Objective: To investigate efficacy and tolerability of the programmed death-ligand 1 (PD-L1) inhibitor avelumab with ramucirumab and paclitaxel in the second line treatment of pts with metastatic EGA (NCT03966118). Methods: In this phase 2 multicenter single-arm clinical trial the reported results are based on a median follow-up of 27.4 months. Patients with previously treated metastatic EGA, adequate organ function, and eligibility for immunotherapy were included. Interventions: Pts with metastatic EGA after progression on platinum/ fluoropyrimidine based palliative first line treatment, checkpoint-inhibitor naive, received ramucirumab 8 mg/kg (d1,15), avelumab 10 mg/kg (d1,15) and paclitaxel 80 mg/m² (d1,8,15) q4w. Results: The pre-specified primary end point was overall survival rate at 6 months (mo) (H0≤50%, H1≥65%). A total of 60 patients (pts) were enrolled, 59 were evaluable (intention to treat, ITT). Participants had a median age of 64.0 yrs (range 18-81) and 80% were men. Baseline Eastern Cooperative Oncology Group performance status was 0 in 23 pts (39.0%) and 1 in 36 pts (61.0%); 29 pts (48.2%) had EGA localized in the esophagogastric junction and 30 in the stomach (51.8%). all pts had received prior platin/ 5-FU based chemotherapy, 40pts (67.8%) had prior taxanes. Central post-hoc biomarker analysis (56 pts) showed PD-1 ligand 1 (PD-L1) combined positive score of 5 or greater in 24 pts (42.9%). The observed overall survival (OS) rate at 6 mo was 71% (95% CI 61-84%) and at 12 mo 43% (95% CI 32-58%). The median OS (ITT) was 10.6 mo (95% CI 8.4-12.8); 9.4 mo (95% CI 7.2-11.7) in pts with PD-L1 CPS &lt; 5 and 14.0 mo (95% CI 6.0-22.1; p = 0.25) in those with PD-L1 CPS≥5. Treatment was generally well tolerated without unexpected toxicities. Translational research identified subgroups with a longer survival possibly due to a higher treatment benefit. Pts with higher than median T cell repertoire (TRB) richness showed an elevated median OS of 20.4 mo compared to pts with lower than median TRB richness (med OS 8.3 mo; HR 0.43, 95% CI 0.23-0.81; p = 0.0079). Pts with lower than median cfDNA burden had a median OS of 19.2 mo compared to pts with higher than median cfDNA (med OS 7.3 mo; HR 0.30, 95% CI 0.16-0.59; p = 0.00022). Conclusions: In this multicenter clinical trial, ramucirumab and paclitaxel combined with avelumab showed favorable efficacy and tolerability in the second line treatment of pts with metastatic EGA. PD-L1 CPS≥ 5, cfDNA below the median or T cell richness above the median seem to predict for even better outcomes with median OS hardly seen before in the second line setting. Clinical trial information: NCT03966118 .

A systematic review of neoadjuvant and definitive immunotherapy in locally advanced head and neck squamous cell carcinoma.

Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) require multi-modality treatment. Immune checkpoint inhibitors (ICIs) are now standard of care in management of recurrent/metastatic HNSCC. However, its role in the definitive and neoadjuvant setting remains unclear. A literature search was conducted that included all articles investigating ICI in untreated locally advanced (LA) HNSCC. Data was extracted and summarised and rated for quality using the Cochrane risk of bias tool. Of 1086 records, 29 met the final inclusion criteria. In both concurrent and neoadjuvant settings, the addition of ICI was safe and did not delay surgery or reduce chemoradiotherapy completion. In the concurrent setting, although ICI use demonstrates objective responses in all published trials, there has not yet been published data to with PFS or OS benefit. In the neoadjuvant setting, combination ICI resulted in superior major pathological response rates compared to ICI monotherapy without a significant increase adverse event profiles, but its value in improving survival is not clear. ICI efficacy appears to be affected by tumour characteristics, in particular PD-L1 combined positive score, HPV status and the tumour microenvironment. There is significant heterogeneity of ICI use in untreated LA HNSCC with multiple definitive concurrent and neoadjuvant protocols used. Resultantly, conclusions regarding the survival benefits of adding ICI to standard-of-care regimens cannot be made. Further trials and translational studies are required to elucidate optimal ICI sequencing in the definitive setting as well as better define populations more suited for neoadjuvant protocols.

Safety evaluation of immune checkpoint inhibitors combined with chemotherapy for the treatment of small cell lung cancer: A meta-analysis of randomized controlled trials.

The addition of immune checkpoint inhibitors (ICIs) to chemotherapy is the new standard of care in the first-line treatment of small cell lung cancer (SCLC). However, although the concomitant use of immunotherapy and chemotherapy can increase the antitumor efficacy, it can also increase toxicity. The present study evaluated the tolerability of immune-based combinations in the first-line treatment of SCLC. Relevant trials were identified by searching electronic databases and conference meetings. Seven phase II and III randomized controlled trials and 3766 SCLC patients were included in the meta-analysis (immune-based combinations=2133; chemotherapy=1633). Outcomes of interest included treatment-related adverse events (TRAEs) and the rate of discontinuation due to TRAEs. Immune-based combination treatment was associated with a higher risk of grade 3-5 TRAEs (odds ratio [OR], 1.16; 95% confidence interval [CI]: 1.01-1.35). Immune-based combinations were associated with a higher risk of TRAEs leading to discontinuation (OR, 2.30; 95% CI: 1.17-4.54). No differences were observed in grade 5 TRAEs (OR, 1.56; 95% CI: 0.93-2.63). This meta-analysis indicates that the addition of immunotherapy to chemotherapy in SCLC patients is associated with a higher risk of toxicity and probably of treatment discontinuation. Tools for identifying SCLC patients that would not benefit from immune-based therapy are urgently needed.

Recent advances in the management of gastric adenocarcinoma patients.

Gastric adenocarcinomas are a significant cause of cancer and cancer death, globally. The curative approach for those with diagnosed localized disease is with surgical resection and an adjunctive approach of perioperative chemotherapy, postoperative adjuvant therapy, or postoperative chemoradiation. Unfortunately, a universal standard approach is lacking for adjunctive therapy which in part has limited the progress achieved in this area. Metastatic disease is common in the Western world at diagnosis. Metastatic disease is treated palliatively with systemic therapy. Targeted therapy has stalled in approvals in gastric adenocarcinomas. Recently, we have seen the exploration of promising targets along with the addition of immune checkpoint inhibitors in select patients. Here, we review recent advances seen in gastric adenocarcinomas.

Long-term outcomes from adding durvalumab to neoadjuvant treatment of operable gastroesophageal cancers: Results from a multicenter study LUD2015-005.

398 Background: Phase III studies have shown a survival benefit for the addition of immune checkpoint inhibitors to conventional chemotherapy for patients with gastroesophageal cancer (GEC). Large scale studies of chemoimmunotherapy prior to and after surgery are under way. We sought to characterise the effects of the PDL1 inhibitor durvalumab (D) with standard neo-adjuvant chemo(radio)therapy regimens in an open label phase I/II study in patients (pts) with operable GEC (LUD2015-005, NCT02735239, EudraCT 2015-005298-19). Methods: In pts identified as suitable for potentially curative surgery we gave D (750mg q2w) alongside their standard treatment. Pts had D only at first then Oxaliplatin and Capecitabine (CapOx) q3w or fluorouracil, leucovorin, oxaliplatin and taxotere (FLOT) starting with the third cycle of D. Chemotherapy and further D were given for 6 (CapOx) or 8 (FLOT) weeks before pts had surgery and for up to 12 further infusions of D after operation. Patients on FLOT could also have more chemotherapy. Pts suitable for chemoradiotherapy (CXRT, CROSS regimen) were offered two cycles of D before starting their treatment, and were able to have up to 12 further cycles after recovering from surgery. Participants were followed for toxicity, response and survival from the time of study enrolment until death, for 3 years or until June 2022 when the study ended. Results: 11 pts received D-CapOx, 9 D-FLOT and 15 D-CXRT. All were evaluable for safety and efficacy. Treatment side effects were as expected for the agents used with diarrhoea, nausea and fatigue the most commonly reported and no new safety signals. 156 of 160 planned pre-op D doses were given. Only 2 out of 35 patients did not have surgery, both due to progressive disease on D-CXRT. 23 of the 33 patients having surgery had post-operative treatment. Amongst 33 evaluable pts 2 (5.7%) and 6 (17.1%) had complete or partial pre-op responses (RECIST) and 3 (8.6%) progression prior to surgery. Tumor regression at surgery (Mandard 1-3) occurred in 24/33 pts. Median recurrence free survival was 25.4 months (mo) (D-CapOx), 32.0 mo (D-FLOT) and not reached (D-CXRT). 2 year survival was 81.8%, 77.8% and 77.8% respectively in the 3 arms. Conclusions: Adding D to standard neo-adjuvant regimens for GEC is well tolerated. Survival times and response rates exceeded those expected for the regimens used (2 year survivals with FLOT 68% and CROSS 67%) in this non-randomised multi-centre trial. Clinical trial information: NCT02735239 .

Enhanced Efficacy of Chemotherapy by Addition of Immune Checkpoint Inhibitors in Stage IV Large Cell Neuroendocrine Carcinoma of the Lung: A Real-World Analysis

Enhanced Efficacy of Chemotherapy by Addition of Immune Checkpoint Inhibitors in Stage IV Large Cell Neuroendocrine Carcinoma of the Lung: A Real-World Analysis