Trials Of Immune Checkpoint Inhibitors Research Articles

Persist or resist: Immune checkpoint inhibitors in EGFR-mutated NSCLC.

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), especially third-generation TKIs, have significantly improved the progression-free survival and overall survival of non-small cell lung cancer (NSCLC) patients with EGFR mutation, TKI resistance is inevitable for most patients. Over the past few years, immune checkpoint inhibitors (ICIs) have significantly improved the survival for EGFR-wild type NSCLC patients. However, no significantly improved benefits were observed with ICI monotherapy in EGFR-mutated patients. EGFR-mutated NSCLC shows more heterogeneity in tumor mutational burden (TMB), programmed cell death-ligand 1 (PD-L1), and immune microenvironment characteristics. Whether ICIs are suitable for EGFR-mutated NSCLC patients remains to be elucidated. In this review, we summarized clinical trials of ICIs or combined therapy in EGFR-mutated NSCLC patients. We further discussed the factors determining the efficacy of ICIs in EGFR-mutated NSCLC patients, the mutation subtypes and microenvironment characteristics of potential responders. More importantly, we provided insights into areas worth further investigation in the future.

Neurologic Outcomes in People With Multiple Sclerosis Treated With Immune Checkpoint Inhibitors for Oncologic Indications.

Immune checkpoint inhibitors (ICIs) are increasingly used against various cancers but are associated with immune-related adverse events (irAEs). Risk of irAEs may be higher in patients with certain preexisting autoimmune diseases, and these patients may also experience exacerbation of the underlying autoimmune disease following ICI initiation. People with multiple sclerosis (MS) have mostly been excluded from clinical trials of ICIs, so data on the safety of ICIs in MS are limited. This study aims to assess the rate of MS activity, as well as neurologic and nonneurologic irAEs in persons with MS treated with ICIs for cancer. Participating sites were invited to this retrospective observational study through the Medical Partnership 4 MS+ listserv. Seven large academic centers participated in the study, each conducting a systematic search of their electronic medical record system for patients with MS and history of ICI treatment. The participating neurologist reviewed each chart individually to ensure the inclusion criteria were met. Demographics and data on MS and cancer history, treatments, and outcomes were abstracted from patient charts using a structured instrument. We identified 66 people with MS (median age 66 years, 73% female, 68% not on disease-modifying therapy for MS) who were treated with ICIs for lung cancer (35%), melanoma (21%), or another oncologic indication. During post-ICI follow-up (median: 11.7 months, range 0.2-106.3 months), 2 patients (3%) had relapse or MRI activity, 3 (5%) had neurologic irAEs, and 21 (32%) had nonneurologic irAEs. At the last follow-up, 25 (38%) participants had partial or complete remission of their cancer, while 35 (53%) were deceased. In this multi-institutional systematic retrospective study of predominantly older patients with MS, most of whom were not on disease-modifying therapy, MS activity and neurologic irAEs following ICI treatment were rare. These data suggest that preexisting MS should not preclude the use of ICIs for cancer in older patients, but the results may not be generalizable to younger patients with active MS. Prospective studies of ICI safety that enroll younger patients with MS are needed.

Immune checkpoint inhibitors for glioblastoma: emerging science, clinical advances, and future directions.

Glioblastoma (GBM), the most common and aggressive primary central nervous system (CNS) tumor in adults, continues to have a dismal prognosis. Across hundreds of clinical trials, few novel approaches have translated to clinical practice while survival has improved by only a few months over the past three decades. Randomized controlled trials of immune checkpoint inhibitors (ICIs), which have seen impressive success for advanced or metastatic extracranial solid tumors, have so far failed to demonstrate a clinical benefit for patients with GBM. This has been secondary to GBM heterogeneity, the unique immunosuppressive CNS microenvironment, immune-evasive strategies by cancer cells, and the rapid evolution of tumor on therapy. This review aims to summarize findings from major clinical trials of ICIs for GBM, review historic failures, and describe currently promising avenues of investigation. We explore the biological mechanisms driving ICI responses, focusing on the role of the tumor microenvironment, immune evasion, and molecular biomarkers. Beyond conventional monotherapy approaches targeting PD-1, PD-L1, CTLA-4, we describe emerging approaches for GBM, such as dual-agent ICIs, and combination of ICIs with oncolytic virotherapy, antigenic peptide vaccines, chimeric antigenic receptor (CAR) T-cell therapy, along with nanoparticle-based delivery systems to enhance ICI efficacy. We highlight potential strategies for improving patient selection and treatment personalization, along with real-time, longitudinal monitoring of therapeutic responses through advanced imaging and liquid biopsy techniques. Integrated radiomics, tissue, and plasma-based analyses, may potentially uncover immunotherapeutic response signatures, enabling early, adaptive therapeutic adjustments. By specifically targeting current therapeutic challenges, outcomes for GBM patients may potentially be improved.

Immune checkpoint inhibitors: A bibliometric analysis of research trends and hotspots based on the most frequently cited clinical trials (2013 - 2021).

To quantitatively and qualitatively evaluate research trends and hotspots for immune checkpoint inhibitors (ICIs), according to the most frequently cited clinical trials. Numerous clinical trials have been carried out using ICIs for activating anti-tumor immunity in cancer patients. The most frequently cited clinical trials have been used as a database for achieving the objectives of this analysis. The most frequently cited articles on ICIs meeting the inclusion criteria were extracted from the Web of Science database. Citation report information including annual outputs, most relevant journals, and country of origin together with burst references, keywords, information on co-occurrence, citation networks, and cluster topics were analyzed using standard bibliometric procedures. A total of 112 most frequently cited articles on clinical trials of ICIs were retrieved for the period 2013 to 2021 of which the journal JAMA Oncology had the highest number of citations. Most studies originated in the U.S., and therefore studies from this country had a determinant effect of the results of the investigation. Burst reference topics included studies on ipilimumab for melanoma, anti-PD-L1 antibody in advanced cancer, anti-PD-1 antibody in cancer, nivolumab combined with ipilimumab or as monotherapy in untreated melanoma, and pembrolizumab for PD-L1 positive non-small-cell lung cancer. Nine clusters were grouped in the citation network. The topic/keywords "cancer", "immunotherapy", "PD-1 blockade", "PD-L1", "expression", "ipilimumab", "nivolumab", "pembrolizumab", and "safety" were the search priorities, whereas "multicenter", "resistance", "adverse events", and "renal-cell carcinoma" were seen as emerging topics in this specific field. The bibliometric analysis of the most frequently cited clinical trials with ICIs provided information on the characteristics of the studies evaluated as well as hotpots and trends in evolving immunopharmacotherapy research on ICIs.

Toxicity surveillance in FDA pivotal registration trials for immune checkpoint inhibitors: Are we missing the mark?

215 Background: Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for a multitude of malignancies, leading to prolonged survival and durable responses. Despite this, a significant number of patients will develop immune-related adverse events (irAEs) with significant associated morbidity and mortality. A retrospective study has previously demonstrated that 28% of patients can develop IrAEs from 6 months up to 2 years after starting therapy (1). Surveillance for toxicity is essential for understanding the long-term risk associated with ICIs. We aimed to analyze the reporting timeframes used in clinical trials of immuno-oncology agents leading to FDA approval. Methods: In this retrospective study, we interrogated the HemeOnc knowledgebase to curate a list of all clinical trial publications leading to FDA approval from 2011 to 2024. We manually selected from this list any trial including an immune checkpoint inhibitor either as monotherapy or in combination with another systemic therapy. The adverse event follow-up time was then extrapolated by manually reviewing the trial publication, supplemental materials or the trial protocol depending on where this information was listed. All trials were categorized based on trial initiation dates. Results: We identified 175 clinical trials leading to FDA approvals, with trial initiation dates ranging from 2004 to 2019. 165 trials were included in the analysis with 10 being excluded due to lack of language regarding follow-up. 62% of the trials included were Phase III trials with the remaining 38% Phase I/II trials. The median follow-up days for all trials across this timeframe was 90, with a range of 28 to 135. The median follow-up time for AE monitoring increased by nearly 30%, rising from 70 days in 2004 to 90 days in 2013. Subsequently, we observed a consistent median follow-up time of 90 days (28 to 130 days) from that point onward, with no further increase. Conclusions: To our knowledge this is the first systematic review of IrAE monitoring in clinical trials leading to FDA approval. In our study we revealed that, despite advancements in the understanding of IrAEs and their potential for late presentation, registration trials leading to regulatory approval remain inadequately designed to capture chronic and delayed immunotherapy toxicities. As these therapies advance into earlier stages of disease with longer life expectancy, it will be critical for regulatory bodies, study sponsors, and trial investigators to either redesign clinical trials or for there to be an alternative method that comprehensively captures the incidence and pattern of late-presenting toxicities. 1. Durbin, ASCO 2023.

Adjuvant treatment for renal cell carcinoma: current status and future.

Renal cell carcinoma (RCC) is resistant to chemotherapy. Adjuvant interferon and tyrosine kinase inhibitors were ineffective. Immune checkpoint inhibitors (ICIs), however, have shed new hope in this setting. In the current review, updated evidence of adjuvant therapy in RCC is summarized. KEYNOTE-564 demonstrated survival benefits of adjuvant Pembrolizumab in RCC. EAU guidelines now recommend adjuvant pembrolizumab to ccRCC patients at an increased risk of recurrence, as defined in the study. At a median follow-up of 24 months, the disease-free survival (DFS) was significantly longer for the Pembrolizumab group than placebo group [DFS 77.3 vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval (95% CI), 0.53-0.87; P = 0.002]. From its updated analysis, at median follow up of 57.2 months, overall survival (OS) benefit of Pembrolizumab was demonstrated (hazard ratio for death, 0.62; 95% CI, 0.44-0.87; P = 0.005). A number of other adjuvant ICI trials have though been negative. Pembrolizumab is currently the only adjuvant therapy for RCC showing survival benefits, amid a number of negative trials on adjuvant immunotherapy. Currently, there is no role for adjuvant tyrosine-kinase inhibitors and radiotherapy for RCC. Meanwhile, a multidisciplinary approach and shared decision-making should be adopted.

Safety of combined ablative radiotherapy and immune checkpoint inhibitors in three phase I trials

BackgroundStereotactic body radiotherapy (SBRT) is safe and effective for treatment of extracranial metastatic disease, but its safety when combined with immune checkpoint inhibitors (ICI) has not yet been comprehensively reported. Here we report adverse events (AEs) associated with combined SBRT and ICI using prospectively-collected data on patients in three trials investigating multi-site SBRT combined with ICI. MethodsPatients were included from three prospective trials of ICI (pembrolizumab; nivolumab/urelumab or nivolumab/cabiralizumab; nivolumab/ipilimumab) with SBRT to 1–4 sites. AEs were recorded prospectively using the CTCAE v4.0. Survival was analyzed using Kaplan-Meier method with a 90-day landmark. Association of patient characteristics with cumulative incidence of AEs was assessed using Fine-Gray regression. Results213 patients were included, with a median follow-up of 10 months. Over the follow-up period, 50 % and 27 % of patients experienced at least one grade ≥ 2 or grade ≥ 3 AE, respectively. Cumulative incidences of grade ≥ 2 and grade ≥ 3 AEs at 6 months were 47 % and 23 %, respectively. Three grade 5 AEs rated “possibly” related to treatment occurred outside the 90-day dose-limiting toxicity window. Landmarked survival analysis of patients with or without grade ≥ 3 AEs showed no significant difference in progression-free or overall survival. Dual-agent ICI was significantly associated with grade ≥ 3 AE. ConclusionThis analysis features the largest prospectively evaluated cohort of patients treated with combination ablative SBRT and ICI to date and provides context for future trial design. We conclude that multi-site SBRT and ICI can be safely co-administered when SBRT is delivered with prioritization of normal tissue constraints.

Placebo immune-related adverse events (irAEs): A neglected phenomenon in cancer immunotherapy trials

PurposeThis study aims to investigate the underexplored prevalence of placebo-reported immune-related adverse events (irAEs) in immune checkpoint inhibitor (ICI) trials. MethodsWe searched public databases for randomized clinical trials (RCTs) involving ICI versus placebo treatments in patients with malignancies. Study characteristics and irAEs occurrences were extracted for meta-analyses using a random-effects model. Main OutcomesProportions of patients reported to experience any grade and grade 3 to 5 placebo irAEs; the risk ratio (RR) of reporting 'false' irAEs in the experiment arm (defined as 'false-irAE ratio', calculated by dividing the proportion of patients documented with irAEs in the placebo arm by that in the experimental arm). Results47 RCTs with 30,119 patients were analyzed. The pooled proportion of patients reported to experience any grade and grade 3 to 5 irAEs among placebo participants was 22.85 % (17.33 %−29.50 %) and 3.40 % (2.35 %−4.63 %), respectively. The pooled proportion of placebo-treated patients who experienced serious irAEs was 0.67 % (0.03 %−1.91 %). Treatment discontinuation and death due to placebo irAEs occurred in 0.69 % (<0.01 %−1.30 %) and 0.12 % (<0.01 %−0.40 %) of patients, respectively. The false-irAE ratio for any grade and grade 3 to 5 irAEs were 0.49 and 0.28. The false-irAE ratio was significantly higher in RCTs with control arms of placebo plus non-immunotherapy than in those with placebo alone (any grade: 0.57 vs. 0.32, P < 0.001; grade 3 to 5: 0.36 vs. 0.12, P = 0.009). ConclusionOur analyses of placebo-treated participants in ICI RCTs document the common occurrence of placebo irAEs. These findings are important for interpreting irAE profiles, avoiding inappropriate therapeutic interventions.

Efficacy and safety of perioperative, neoadjuvant or adjuvant immunotherapy alone or in combination chemotherapy in early-stage non-small cell lung cancer: A systematic review and meta-analysis of randomized clinical trials.

8025 Background: Adjuvant (AD), neoadjuvant(NE), or perioperative(PE) immunotherapy in early-stage non-small cell lung cancer (eNSCLC) has been validated in multiple clinical trials in recent years. However, the comparations of efficacy and safety among three treatment modalities remain unclear. Methods: The PubMed, Embase, and Cochrane databases were searched for randomized controlled trials (RCTs) of immune checkpoint inhibitors (ICI) plus chemotherapy (CT) for eNSCLC. We calculated hazard ratios (HRs) or advantage ratios (ORs) for binary endpoints with 95% confidence intervals (CIs). Network meta-analysis was performed using a Bayesian framework to indirectly compare the three treatment modalities. Results: A total of 11 RCTs (2 NE, 6 PE, and 3 AD) including 6951 NSCLC patients were included. Among the three treatment modalities, indirect comparisons revealed that efficacy differed between PE and AD immunotherapy was only observed in the EFS/DFS (HR=0.68, 95%CI: 0.49-0.89). Compared with the control group, NE/PE immunotherapies significantly improved pathologic complete response (pCR) (OR=7.56, 95%CI: 5.24-10.92), major pathologic response(MPR) (OR=5.46, 95%CI: 3.97-7.51), EFS(HR=0.58, 95% CI: 0.50-0.67), and AD immunotherapy significantly improved DFS (HR=0.83, 95% CI: 0.73-0.94). No significant OS difference was observed in NE and AD setting (HR=0.62, 95% CI: 0.36-1.05; HR=0.90, 95% CI: 0.76-1.06, respectively), and only PE immunotherapy showed OS benefits(HR=0.67, 95%CI: 0.54-0.84). In addition, EFS was significantly improved in the PE treatment subgroup regardless of stage, pathologic response, histology, PD-L1 expression, and gender (Table), but no significant benefit in the EGFRm NSCLC subgroup(HR=0.54, 95% CI: 0.21-1.43). AD (OR 1.52, 95% CI: 1.01-2.30) and PE (OR 1.29, 95% CI: 1.08-1.54) immunotherapies were significantly associated with higher grade ≥3 adverse events (AEs) compared with controls. Rash was the most common grade ≥3 irAEs. Conclusions: PE immunotherapy seems to be more effective than NE and AD immunotherapy in three treatment modes. NE and PE immunotherapy significantly improved pCR, MPR, EFS, and AD immunotherapy significantly improved DFS in eNSCLC patients in comparison with the control group, but only PE immunotherapy significantly improved OS. [Table: see text]

Validation of PD-L1 as a predictive biomarker of response in operable gastroesophageal adenocarcinoma: A meta-analysis and meta-regression of neoadjuvant chemoimmunotherapy trials.

4065 Background: Perioperative chemotherapy (ChT) is a standard for operable gastroesophageal adenocarcinoma (GEA). The addition of immune checkpoint inhibitors (ICIs) has improved pathological complete response (pCR) with unclear survival advantages in an unselected population. In the advanced setting, PD-L1 is a validated biomarker of response to ICIs. We aimed to assess its predictive role in the early stages wherein remains unexplored. Methods: We conducted a systematic review of randomised clinical trials (RCTs) of neoadjuvant or peri-operative ChT +/- ICIs in non-metastatic GEA, published between 2006-2024. Biomarker-unselected phase 2/3 or phase 3 RCTs with an active comparator were selected. Odds ratios (ORs) for pathological response (defined as pCR, ypT0, or ypT≤1), the primary outcome of this meta-analysis, were extracted and analysed using a random-effect meta-analysis. Subgroup analysis (ICI-ChT versus ChT) was performed to estimate the pooled effect of peri-operative ICIs on pathological response. Sensitivity analyses were performed to account for between-study heterogeneity. We then extracted pCR data by PD-L1 (cutoffs 1, 5, 10) from phase 2 trials of neoadjuvant ICIs+ChT or chemoradiotherapy (CRT) published between 2006-2024. Weighted Pearson trial-level correlation and a meta-regression model were used to assess the relationship of PD-L1 with pCR. Results: Nine RCTs were eligible for the analysis, one of which had two experimental arms contributing to two comparisons. Of 5359 included patients, 1302 received ICI-ChT and 4057 systemic ChT. ICI-ChT showed a significant improvement in pathological response (pooled OR 2.90, 95% CI 1.81-4.63, p&lt;0.001) with a larger effect compared to ChT-only trials (pooled OR 1.40, 95% CI 1.10-1.79, p=0.007). Results were consistent in sensitivity analyses of pCR-only, non-Asian, and since-FLOT studies. Fourteen studies were included in the phase 2 trials dataset (n=10 ICI+ChT and n=4 ICI+CRT) accounting for 708 patients receiving ICIs. PD-L1 showed a moderate positive correlation with pCR, stronger for higher cut-offs (weighted R for cut-offs 1, 5, and 10: 0.33, 0.51, and 0.65, respectively) and after exclusion of CRT trials (weighted R for cut-offs 5 and 10: 0.67 and 0.99, respectively). In a mixed-effect meta-regression model, PD-L1 ≥5 was a significant predictor of response (effect size [ES]: 0.71, 95% CI, 0.29-1.13, p=0.001), even after accounting for the backbone treatment (ChT versus CRT) (ES: 0.60, 95% CI, 0.20-1.00, p=0.003). Conclusions: Neoadjuvant ICI-ChT consistently improves pathological response in operable GEA, particularly in PD-L1-positive tumours. PD-L1 ≥5 appears a significant biomarker of pCR in non-metastatic GEA, supporting stratification by PD-L1 and biomarker-selected trials for evaluation at the individual patient level.

Impact of sex on immune-related adverse events in patients with melanoma.

e21548 Background: The clinical success of immune checkpoint inhibitors (ICIs) has predominantly conquered the modern scenario of the fight against cancer. Sex is a well acknowledged biological variable that affects immune responses to both self and foreign antigens. Indeed, recent meta-analyses of phase II and III trials of ICIs have focused on sex-related prognostic outcomes, reporting that both the overall and the progression-free survival are greater for males than females in melanoma, urothelial, and non-small-cell lung cancer. Conversely, very few studies have investigated the impact of sex on possible correlation with ICIs adverse events (AEs). Aim of this study is to identify female-male (F-M) differences in AEs developed in melanoma patients (pts) during anti-PD-1 treatment and to explore the related biological mechanism through a gene profiling analysis. Methods: Melanoma pts underwent anti-PD-1 delivery as adjuvant as well as first line treatment, who developed AEs from grade 2 onwards, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, have been involved in the study. Gene profiling analysis was performed using NanoString IO360 panel, RNA was extracted from whole blood. Female-male differences in AEs were tested by Fisher's exact test. Volcano plot was used for graphical gene expression of fold change. Results: A total population of 161 melanoma pts has been analysed. With a total of 73 female pts and 88 male pts, arthralgia and nausea resulted as significant statistically different between female and male (p-value = 0.03 and &lt; 0.01 respectively), with female pts most affected. A specific gene signature in female who developed arthralgia has been identified and characterized by the following genes: BCL2, EGFR, WNT10A, CTSS, IFITM2, HLA-B. These genes are involved in intracellular pro-apoptotic pathways activation and innate and adaptive immune responses activation. It has been already acknowledged that females are able to mount stronger innate and adaptive immune responses than males, which results in faster clearance of pathogens and greater vaccine efficacy in females than in males, but also explains the greater incidence of inflammatory and autoimmune diseases in females. Conclusions: In this study, we found a significant statistically sex difference of arthralgia and nausea during anti- PD-1 treatment in melanoma pts. Arthralgia in female is associated with a peculiar gene signature, which needs further investigation. Greater consideration should be given for researches that address the biological (sex) as well as sociocultural (gender) causes of F-M discrepancies in cancer immunotherapy. International collaborations have to be hugely promoted to increase knowledge in this field.

Predictive capacity of immune-related adverse events and cytokine profiling in neoadjuvant immune checkpoint inhibitor trials for head and neck squamous cell carcinoma.

Certain low-level immune-related adverse events (irAEs) have been associated with survival benefits in patients with various solid tumors on immune checkpoint inhibitors (ICIs). We aimed to investigate the association between irAEs and response to neoadjuvant ICIs in patients with head and neck squamous cell carcinoma (HNSCC) and to identify differences in circulating cytokine levels based on irAE status. This was a retrospective cohort study including three neoadjuvant clinical trials from July 2017 to January 2022: NCT03238365 (nivolumab ± tadalafil), NCT03854032 (nivolumab ± BMS986205), NCT03618654 (durvalumab ± metformin). The presence and type of irAEs, pathologic treatment response, and survival were compared. Canonical linear discriminant analysis (LDA) was performed to identify combinations of circulating cytokines predictive of irAEs using plasma sample multiplex assay. Of 113 participants meeting inclusion criteria, 32 (28.3%) developed irAEs during treatment or follow-up. Positive p16 status was associated with irAEs (odds ratio [OR] 2.489; 95% CI 1.069-6.119; p = 0.043). irAEs were associated with pathologic treatment response (OR 3.73; 95% CI 1.34-10.35; p = 0.011) and with higher OS in the combined cohort (HR 0.319; 95% CI 0.113-0.906; p = 0.032). Patients with irAEs within the nivolumab cohort had significant elevations of select cytokines pre-treatment. Canonical LDA identified key drivers of irAEs among all trials, which were highly predictive of future irAE status. irAEs are associated with response to neoadjuvant ICI therapy in HNSCC and can serve as clinical indicators for improved clinical outcomes. irAEs can be predicted by concentrations of several circulating cytokines prior to treatment.

Abstract PO2-20-11: Safety and efficacy of KEYNOTE-522 in combination with anti-retroviral therapy in a patient with HIV and triple-negative breast cancer

Abstract Introduction: Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2), accounting for about 15% of all BC. TNBC is more aggressive than other BC with a higher risk of recurrence and mortality. The current standard of care for high-risk, early-stage TNBC based on the KEYNOTE-522 trial is neoadjuvant multidrug chemotherapy (paclitaxel and carboplatin [TCb] weekly x 12 weeks and doxorubicin and cyclophosphamide [AC] Q3 weeks) with pembrolizumab (P). The trial demonstrated patients who received chemotherapy plus P had a higher pathological complete response and event-free survival compared to patients who received chemotherapy plus placebo. However, the trial excluded patients with any autoimmune disease requiring treatment within 2 years, a diagnosis of immunodeficiency or steroids within 7 days before the first treatment, or a known history of human immunodeficiency virus (HIV). While limited data exist on immune checkpoint inhibitors (ICI) in patients with immunodeficiencies, subsequent data demonstrate that patients with HIV have similar efficacy and immune-related adverse events (irAE) compared to patients without HIV, and 2017 consensus recommendations encouraged broader eligibility in clinical trials to include patients with HIV. We present one of the first reported clinical cases of a patient with HIV diagnosed with stage IIB TNBC, treated per KEYNOTE-522 and anti-retroviral therapy (ART). Clinical Case: A 55-year-old female with a medical history significant for HIV, self-detected a mass in her left breast. Diagnostic imaging demonstrated a suspicious 4.0 cm mass in the left breast without adenopathy. An ultrasound-guided biopsy of the mass revealed grade 3 invasive ductal carcinoma with ER 0%, PR &amp;lt; 1%, and HER-2 1+. The clinical stage was cT2N0M0, prognostic stage IIB. Genetic testing was positive for germline BRCA2 pathogenic variant. HIV PCR &amp;lt; 20 copies/mL and CD4 count 1.298 K/uL prior to neoadjuvant chemotherapy. The patient was adherent to HIV ART with bictegravir, emtricitabine, and tenofovir alafenamide. The patient received KEYNOTE-522, including 11 cycles of TCb-P, followed by four cycles of AC-P. Following neoadjuvant treatment, the patient underwent a left segmental mastectomy and sentinel lymph node biopsy and achieved a pathological complete response. She completed left whole breast radiation (RT) with 3DCRT plus 3DCRT tumor bed boost to a total dose of 48.06 cGy and one-year of adjuvant P. Treatment-related adverse events included grade 4 febrile neutropenia after cycle one AC without growth factor, requiring a 5-day hospitalization; and grade 3 peripheral neuropathy, resulting in discontinuation of week 12 of TCb. The patient also developed paronychia, and a pulmonary embolism after week 11 of TCb. She had no irAE. Radiation-related adverse events included grade 1 left breast dermatitis and fatigue and mild left breast soreness. Discussion: Among the subset of patients diagnosed with TNBC, the percentage of patients with HIV or immunodeficiency receiving active BC treatment is low. Safety and efficacy data for novel cancer therapeutics including ICI are limited since historically patients with HIV and other immunodeficiency states were excluded from trials. Anti-PD-1 ICI has become a key part of the standard of care for the treatment of breast cancer. Patients with HIV experience rare infectious complications and have a life expectancy near the general population with ART. We support the inclusion of patients with HIV in future clinical trials for TNBC and/or ICI and recommend treatment of patients with HIV and TNBC per standard of care in multi-disciplinary collaboration with HIV clinicians. Citation Format: Stephanie Haddad, Stephanie Graff, Matthew Hadfield, Yihong Wang, Charu Taneja, Kara Leonard, Martha Sanchez, Robert Ward, Ana Lourenco, Mary Anne Fenton. Safety and efficacy of KEYNOTE-522 in combination with anti-retroviral therapy in a patient with HIV and triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-11.

Management of Hepatitis B Virus and Hepatitis C Virus Infections in Patients with Cancer Receiving Immune Checkpoint Inhibitors.

Patients with cancer with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are excluded from many cancer clinical trials of immune checkpoint inhibitors (ICIs). Therefore, data are limited regarding the management of HBV and HCV infections in patients with cancer treated with ICIs. To address this gap, we reviewed the literature on management of HBV and HCV infections in patients with cancer receiving ICIs. We searched MEDLINE and PubMed for all original research articles, case reports, and systematic reviews published in English between Jul 2013 and Jul 2023 on patients with cancer with HBV or HCV infection receiving ICIs. We found 28 studies (three prospective clinical trials, seven retrospective cohort studies, nine retrospective case series, and nine case reports) that evaluated the safety of ICI therapy in patients with HBV infection and cancer. The overall rate of HBV reactivation was 1.4% (38/2799), and no HBV-related deaths were reported. The frequency of HBV reactivation in patients with chronic and past HBV infections was 2% (35/1667) and 0.3% (3/1132), respectively. The risk of HBV reactivation was significantly higher among patients with chronic HBV infection not receiving antiviral prophylaxis than among those receiving antivirals (17% vs 1%, p < 0.05). Based on high-quality evidence, for patients with chronic HBV infection, antiviral prophylaxis is recommended before ICI therapy initiation. For patients with past HBV infection, monitoring and on-demand antiviral treatment are sufficient. We found 11 studies (five clinical trials, five retrospective studies, and one prospective observational study) that evaluated the safety of ICI therapy in patients with HCV infection and cancer. The overall rate of HCV reactivation was 0.5% (2/387), and no HCV-related deaths were reported. HCV reactivation occurs primarily in patients receiving immunosuppressants for ICI-related toxic effects. ICIs are safe for HCV-infected patients with solid tumors. Chronic HBV or HCV infection should not be considered a contraindication for ICI therapy. Specific risk assessment, monitoring, and management strategies are necessary to reduce the risk of ICI-related liver injury in patients with cancer and chronic HBV or HCV infection.

Immune Checkpoint Inhibitors in Geriatric Oncology.

This manuscript will update prior reviews of immune checkpoint inhibitors (ICIs) in light of basic science, translational, and clinical discoveries in the field of cancer immunology and aging. ICIs have led to significant advancements in the treatment of cancer. Landmark trials of ICIs have cited the efficacy and toxicity experienced by older patients, but most trials are not specifically designed to address outcomes in older patients. Underlying mechanisms of aging, like cellular senescence, affect the immune system and may ultimately alter the host's response to ICIs. Validated tools are currently used to identify older adults who may be at greater risk of developing complications from their cancer treatment. We review changes in the aging immune system that may alter responses to ICIs, report outcomes and toxicities in older adults from recent ICI clinical trials, and discuss clinical tools specific to older patients with cancer.

Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions.

Colorectal cancer (CRC) is a complex disease with diverse etiologies and clinical outcomes. Despite considerable progress in development of CRC therapeutics, challenges remain regarding the diagnosis and management of advanced stage metastatic CRC (mCRC). In particular, the five-year survival rate is very low since mCRC is currently rarely curable. Over the past decade, cancer treatment has significantly improved with the introduction of cancer immunotherapies, specifically immune checkpoint inhibitors. Therapies aimed at blocking immune checkpoints such as PD-1, PD-L1, and CTLA-4 target inhibitory pathways of the immune system, and thereby enhance anti-tumor immunity. These therapies thus have shown promising results in many clinical trials alone or in combination. The efficacy and safety of immunotherapy, either alone or in combination with CRC, have been investigated in several clinical trials. Clinical trials, including KEYNOTE-164 and CheckMate 142, have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab, respectively, for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC. Unfortunately, these drugs benefit only a small percentage of patients, with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients. To this end, primary and secondary resistance to immunotherapy remains a significant issue, and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response. This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC. The underlying rationale, challenges faced, and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

Abstract 5461: Antecedent STING agonist therapy improves tumor response to chemotherapy in murine models of osteosarcoma

Abstract Little improvement has been made in outcomes for pediatric patients with osteosarcoma in decades. Cytotoxic chemotherapy alone is insufficient for cure and upfront complete surgical resection is usually required to achieve long-term survival. Better systemic therapies are needed. Osteosarcoma is characterized by a high degree of genomic instability that would suggest these tumors have sufficient neoantigen burden to be immunogenic and responsive to immunotherapy, but trials of immune checkpoint inhibitors in osteosarcoma have shown poor effectiveness. Although immunotherapy drugs targeting the adaptive immune system have worked poorly, we hypothesize that an innate immune adjuvant - stimulator of interferon response cGAMP interactor 1 (STING) agonist - in combination with cytotoxic chemotherapy would improve chemotherapy effectiveness and immune-mediated tumor clearance, particularly given the abundance of innate immune cells in the microenvironment of these tumors. Using two different immune-competent in vivo murine models of osteosarcoma (K7M2 in BALB/c mice and F420 in C57BL/6 mice), we challenged mice with tumor cells via subcutaneous or intratibial injection. In all experimental replicates, we observed improved tumor regression in mice treated with intratumoral STING agonist followed by intraperitoneal treatment with carboplatin. Responses included complete tumor response in up to 40% of treated mice. Treatment with STING agonist alone or carboplatin alone only delayed tumor growth compared to untreated controls. Additionally, mice treated first with carboplatin and then with STING agonist demonstrated an initial modest response to treatment, but ultimately exhibited tumor progression, suggesting an importance to the sequence of STING agonist administration. In vitro treatment of K7M2 and F420 cells with STING agonist showed a tumor-intrinsic transient increase in expression of pro-inflammatory mediators Cxcl10, Ccl5, and Ifnb 4 hours after STING exposure. Flow cytometry analysis of K7M2 tumors demonstrated increased infiltration of STING/carboplatin-treated tumors with CD8+/IFNγ+ lymphocytes and CD11b+/MHCII+/F480+ tumor-associated macrophages. Interestingly, these tumors also demonstrated an increased quantity of CD11b+/MHCII-/F480-/Ly6Glo/Ly6C+ myeloid-derived suppressor cells despite their favorable clinical response. Our findings suggest that intratumoral STING agonist therapy stimulates tumor-intrinsic and tumor-extrinsic pro-inflammatory mediators that improve the tumor response to treatment with carboplatin. Ongoing studies are further investigating the tumor-intrinsic and extrinsic mediators that are driving this improved response to therapy. Citation Format: Erin E. Resch, Emily Kulp, Michele Doucet, Alice Recho, Brian H. Ladle. Antecedent STING agonist therapy improves tumor response to chemotherapy in murine models of osteosarcoma [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 5461.

Abstract 3722: Immunotherapy efficacy in advanced hepatocellular carcinoma in a diverse and underserved population in the United States

Abstract The incidence of hepatocellular cancer (HCC) in the Bronx is 61% higher than the rest of New York State. Underserved populations are not well represented in clinical trials of immune checkpoint inhibitors. The purpose of this study is to analyze the efficacy of immunotherapy treatment in a diverse and underserved patient population in the Bronx. Study demographics include 194 patients treated with ICI at the Montefiore Einstein Comprehensive Cancer Center (MECCC) between 2017 and 2022. A retrospective electronic medical record (EMR) review was conducted of all adult patients and this sample size was identified as having advanced HCC treated with immunotherapy. Outcome parameters such as overall survival and disease control rate assessed by radiologists using the Modified Response Evaluation Criteria in Solid Tumors (mRECIST 1.1) were reported. Survival was evaluated using parameters such as baseline serum alpha-fetaprotein(AFP) level, its evolution at the 3-month re-evaluation mark, the Child-Pugh(CP) class and MELD-Na score at the time of diagnosis. Categorical variables were analyzed by Chi-squared test and survival was analyzed using Kaplan-Meier (KM) curves. MECCC patients were 40.7% Hispanic and 20.6% Black, compared with 3% and 2% respectively in the landmark IMbrave 150 study. Median overall survival (mOS) on ICI was 9.0 months, 25.0 months for the 100 (51.5%) favorable-prognosis Child Pugh A (CPA) patients included in HCC clinical trials. Disease control rate (DCR) was 58.5% among 123 evaluable patients per mRECIST 1.1. Baseline liver function, as defined by CP and Model for End Stage Liver Disease-Sodium (MELD-Na), correlated with survival (p&amp;lt;0.001). Hepatitis C Virus (HCV) and alcoholism were over-represented relative to National Cancer Institute (NCI) data (56.2% vs 4.7% and 38.7% vs 8.2%, respectively). HCV treatment correlated with prolonged survival in infected patients (p=0.0017). AFP decline correlated with response (p=0.001). Hispanic patients lived longer when clinical variables were controlled for (mOS 52 vs 23 months; p=0.011). In summary, our patient population differed significantly in racial composition and etiology of liver disease from clinical trial populations on which ICI was tested. In an underserved HCC population, ICI yielded a DCR of 58.5% and low rates of severe toxicity. This work highlights ICI efficacy in minority groups, a need for earlier HCC diagnosis and for studies of genetics and environmental factors in Hispanics with HCC. Citation Format: Fernand Bteich, Lydia Bioh, Kush Desai, Chenxin Zhang, Anahat Kaur, Rahel A. Levy, Aaron Wang, Sharmin Sultana, Andreas Kaubisch, Milan M. Kinkhabwala, Sarah Bellemare, Shabnam A. Fidvi, Devaraju Kanmaniraja, Robert G. Berkenblit, Jee-Young Moon, Adebola A. Adedimeji, Clara Y. Tow, Yvonne M. Saenger. Immunotherapy efficacy in advanced hepatocellular carcinoma in a diverse and underserved population in the United States [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 3722.

Cytoreductive nephrectomy in the era of immune checkpoint inhibitors: a US Food and Drug Administration pooled analysis.

This pooled analysis of patient-level data from trials evaluated the clinical outcomes of patients with metastatic renal cell carcinoma with or without cytoreductive nephrectomy before a combination of immune checkpoint inhibitor and antiangiogenic therapy. Data from 5 trials of immune checkpoint inhibitors plus antiangiogenic therapy were pooled. Only patients with stage 4 disease at initial diagnosis were included to ensure that nephrectomy was performed for cytoreductive purposes and not to previously treat an earlier stage of disease. The effect of cytoreductive nephrectomy before immune checkpoint inhibitor therapy on outcomes was evaluated using the Kaplan-Meier method and a Cox proportional hazards regression model, adjusted for age, sex, risk group, performance status, and the presence of sarcomatoid differentiation. A total of 981 patients were included. The estimated median progression-free survival with and without nephrectomy was 15 and 11 months, respectively; the adjusted hazard ratio was 0.71 (95% confidence interval = 0.59 to 0.85). The estimated median overall survival with and without nephrectomy was 46 and 28 months, respectively; the adjusted hazard ratio was 0.63 (95% confidence interval = 0.51 to 0.77). Objective response was 60% of patients with vs 46% of patients without cytoreductive nephrectomy. Patients with metastatic renal cell carcinoma who undergo cytoreductive nephrectomy before immune checkpoint inhibitor plus antiangiogenic therapy had improved outcomes compared with patients without cytoreductive nephrectomy. Selection factors for cytoreductive nephrectomy may be prognostic and could not be fully controlled for in this retrospective analysis. Prospective determination of and stratification by prior cytoreductive nephrectomy may be considered when designing clinical trials to assess the impact of this factor on prognosis.

Correlations of response rate and progression-free survival with overall survival in immunotherapy trials for metastatic non-small-cell lung cancer: an FDA pooled analysis

Radiographic changes might not fully capture the treatment effects of immune checkpoint inhibitors (ICIs). We aimed to assess correlations of overall response rate and progression-free survival with overall survival in trials of ICIs for metastatic non-small-cell lung cancer (NSCLC). To assess trial-level and patient-level correlations of overall response rate and progression-free survival with overall survival, we conducted a pooled analysis of first-line randomised trials (including patients aged ≥18 years with metastatic squamous and non-squamous NSCLC and an Eastern Cooperative Oncology Group performance status of 0-1) submitted to the US Food and Drug Administration from June 24, 2016, to March 16, 2021. Eligible trials evaluated at least one ICI in the experimental group versus chemotherapy in the control group. At the trial level, we used weighted linear regression to derive coefficients of determination (R2). At the patient level, we used Cox proportional hazards models to compare overall survival between responders versus non-responders per Response Evaluation Criteria in Solid Tumours (version 1.1). A total of 13 trials including 9285 patients evaluated ICIs alone or in combination with chemotherapy versus chemotherapy alone. At the trial level, the R2 was 0·61 (95% CI 0·32-0·84) for correlation of overall response rate with overall survival and 0·70 (0·40-0·89) for correlation of progression-free survival with overall survival. Correlations ranged from weak to moderate when evaluating subgroups by PD-L1 expression and were consistent across trials evaluating ICIs alone or in combination with chemotherapy. At the patient level, responders had longer overall survival than non-responders (hazard ratio [HR] 0·28 [95% CI 0·26-0·30]). Among responders, overall survival was longer in patients enrolled in experimental groups than in control groups (HR 0·54 [95% CI 0·48-0·61]). Correlations of overall response rate and progression-free survival with overall survival were generally moderate in this pooled analysis. The findings support routine analysis of mature overall survival data, where feasible, in first-line randomised trials of ICIs for metastatic NSCLC. US Food and Drug Administration.