Use Of Immune Checkpoint Inhibitors Research Articles

Abstract PO2-27-12: Genomic determinants of benefit to nivolumab (NIVO) plus low dose ipilimumab (IPI) among patients (pts) with hypermutated HER2-negative metastatic breast cancer (MBC): results of NIMBUS trial

Abstract Background: Genomic determinants of benefit to immune checkpoint inhibitors (ICI) among pts with MBC and high tumor mutational burden (TMB-H) are largely unknown. NIMBUS was an open-label, single-arm, multicenter, phase 2 study assessing the efficacy of NIVO 3 mg/kg intravenously every 14 days plus IPI 1 mg/kg IV every 6 weeks in pts with TMB-H HER2-negative MBC. The objective of this current study was to evaluate genomic profiling of pts included in NIMBUS and its association with benefit to ICI. Methods: In NIMBUS, eligible pts were required to have measurable HER2-negative MBC, TMB ≥9 Mut/Mb assessed by a cancer-gene panel evaluating > 300 genes and performed in a CLIA-certified laboratory, and 0-3 prior lines of chemotherapy in the advanced setting. The primary objective was overall response rate (ORR) according to RECIST 1.1. Secondary objectives include progression-free survival (PFS), and overall survival (OS). We performed genomic analyses on the pre-treatment tissue, and on baseline and on treatment plasma from pts run on the Foundation Medicine Inc (Boston, MA) FoundationOne®CDx (F1CDx®) and FoundationOne®Liquid CDx (F1LCDx®) panel, respectively. Results: A total of 30 pts (21 with estrogen receptor (ER)-positive and 9 with triple-negative breast cancer) were included in this study. After a median follow-up of 30.6 months, 6 pts (20%) achieved partial response (PR) for a confirmed ORR of 20% (95% CI: 7.7-38.6%). Exploratory analyses did not reveal differences in ORR based on ER status, PD-L1 status, or stromal TIL. The median PFS was 1.4 months (95% CI: 1.3 – 4.6), and the median OS was 16.9 months (95% CI: 7.1-not reached). Pts who achieved PR had a 3-year OS of 75% versus 25% in non-responders. A total of 29 pts (6 responders and 23 non-responders) had at least one pre-treatment genomic panel performed: 16 had both, 5 had pretreatment F1CDx only and 8 had F1LCDx panel only. Blood TMB (bTMB) was highly correlated with tissue TMB by F1CDx (r = 0.95). Using data from the most recent genomic panel available, (24 for baseline blood, and 5 for pretreatment tissue), the most frequently mutated genes ( > 30%) in this population were: TP53 (66%); PIK3CA (45%), ESR1 (35%), CDH1 (35%), ROS1 (31%). ESR1 and PTEN mutations were associated with absence of PR while PALB2 was associated with objective response. We observed a significant correlation between ESR1 mutations and a decrease in OS among pts with ER+ disease. Among the entire 29 pts, a negative correlation between PTEN with PFS and OS, and positive correlation between PALB2 with PFS was observed (Table). Among the 24 pts with baseline F1LCDx panel evaluable, the median TMB was 7.6 Mut/Mb ([interquartile range 0.0–113.8). Median TMB was 8.9 Mut/Mb and 41.7 Mut/mB among pts without and with PR, respectively. Baseline TMB > 20 mut/Mb was found in all pts with PR and in one of those without response. Paired serial blood samples demonstrated that among responding pts, TMB was significantly reduced from baseline to end of treatment (EOT) compared to those with no clinical benefit [n=16, p=0.0015]. Lastly, the tumor fraction (TF) estimates from 7 paired baseline to EOT samples demonstrated that all responders had a decrease or no change in TF compared to an increase in non-responders [n=7, p=0.017]. Conclusion: In the NIMBUS trial, all pts with PR to NIVO plus low dose IPI had a TMB > 20 Mut/Mb and had a decrease in TMB during treatment. ESR1 and PTEN mutations were associated with lack of benefit, while PALB2 mutation was associated with increased benefit. If validated, these results could help tailor the use of ICI among pts with TMB-H MBC. Association between genomic alterations in ESR1, PTEN and PALB2 and benefit to nivolumab and low dose ipilimumab among patients with HER2-negative MBC and TMB-H HR: hazard ratio; MBC: metastatic breast cancer; mOS: median overall survival (months); mPFS: median progression-free survival (months); TMB-H: tumor mutational burden above > 9 mutations/megabase. Citation Format: Romualdo Barroso-Sousa, Tyler Chinsky, Tianyu Li, Sangeetha Reddy, Leisha Emens, Beth Overmoyer, Saud AlDubayan, Hoyin Chu, Paulina Lange, Julie Kasparian, Ameer Basta, Molly DiLullo, Victoria Attaya, Melissa Hughes, Nancy Lin, Nabihah Tayob, Rinath Jeselsohn, Elizabeth Mittendorf, Sara Tolaney. Genomic determinants of benefit to nivolumab (NIVO) plus low dose ipilimumab (IPI) among patients (pts) with hypermutated HER2-negative metastatic breast cancer (MBC): results of NIMBUS trial [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 PO2-27-12.

Abstract PO2-20-07: A case report of a severe cutaneous adverse event in triple negative breast cancer treated with chemoimmunotherapy

Abstract Introduction Cutaneous adverse events related to immune checkpoint inhibitors (ICI) are common and most are mild. However, numerous case reports have documented severe ICI-related skin-toxicities such as Stevens-Johnsons Syndrome (SJS) most commonly among patients with melanoma and lung cancer as immunotherapy has now become a mainstay of treatment in these tumors. The use of ICIs in breast cancer treatment has only recently become standard of care for treatment of metastatic and high risk early-stage triple negative breast cancer with the publication of two landmark clinical trials, KEYNOTE-355 and KEYNOTE-522, respectively. While these trials report low rates of severe skin reactions, little is known about ICI-related severe skin toxicities in patients with breast cancer. Case description A 58-year-old female with clinical stage IIB (cT2N0M0) triple negative breast cancer was undergoing neoadjuvant treatment with pembrolizumab, an anti-programmed death (PD-1) monoclonal antibody, coupled with a chemotherapy back-bone of 12 weekly treatments of carboplatin and paclitaxel followed by 4 cycles of doxorubicin and cyclophosphamide. She developed an erythematous and itchy rash on the right breast and axilla approximately 61 days into her treatment course after having received her fourth dose of pembrolizumab. Over the next 10 days, she developed progression of the rash with painful red papules coalescing into reticulated plaques and dusky blistering of the skin involving the right arm, axilla, abdomen, inguinal folds, thigh, and back, totaling < 10% total body surface area. Notably, the rash did not have mucosal involvement. She was hospitalized for close monitoring and treatment. A punch biopsy of the rash revealed interface dermatitis with areas of full thickness skin necrosis consistent with erythema multiforme, SJS, toxic epidermal necrolysis (TEN), or a fixed drug eruption. Her skin continued to slough in the distribution of rash and a diagnosis of SJS was made. The patient had no response to initial treatment with high dose steroids. Cyclosporine was added, resulting in rapid improvement of her rash. The patient’s neoadjuvant treatment was stopped given the grade 3 SJS she experienced. Despite this truncated neoadjuvant treatment, she had excellent clinical response as her tumor was no longer palpable. She proceeded with a partial mastectomy and sentinel lymph node biopsy. Pathology revealed a pathological complete response. She did not receive any further systemic therapy in the adjuvant setting. Three months later, she was evaluated in clinic without evidence of SJS on physical exam. She was rapidly tapered off cyclosporine over one week without recurrence of her rash. Discussion Severe cutaneous adverse events related to ICIs remains an emerging area of study. In SJS, drug-specific CD8+ T lymphocytes utilize granulysin to mediate keratinocyte apoptosis. It is hypothesized that the blocking of the PD-1/PD-L1 interaction by ICIs results in the disruption of T-cell homeostasis leading to self-directed cytotoxic and inflammatory reactions and ultimately epidermal detachment. In contrast, Molina et al 2020 postulate that such ICI-related skin reactions may represent a separate clinical entity from SJS. In their case report of seven patients, they propose the term “progressive immunotherapy-related mucocutaneous eruption” (PIRME), which the authors suggest is characterized by delayed symptom onset, mild initial presentation, rare ocular involvement, benign clinical course, and favorable treatment response. Further characterization of ICI-related cutaneous adverse events is needed to understand the disease course, optimal treatment, and importantly, implications for re-challenging patients with immunotherapy. Clinicians taking care of breast cancer patients treated with ICIs need to be educated to recognize the associated skin toxicities as patients can rapidly worsen without appropriate treatment. Citation Format: Annie Zhang, Mara Beveridge, Bahar Moftakhar. A case report of a severe cutaneous adverse event in triple negative breast cancer treated with chemoimmunotherapy [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 PO2-20-07.

Abstract PO2-20-10: Exceptional long-term disease control on pembrolizumab monotherapy in a patient with TMB-high PMS2-mutated MMR-deficient triple negative breast cancer brain metastasis

Abstract Introduction The brain is among the most common sites of breast cancer (BC) spread. Prognosis of BC brain metastasis (BCBM) differs by receptor subtype, with poorest median overall survival (OS) for triple-negative (TN) BCBM at under 5 months. Though treatment guidelines have evolved in recent years, most strategies have focused on local therapies including surgery and stereotactic radiotherapy (SRT), rather than on systemic agents. The 2020 FDA approval of pembrolizumab (pembro) for patients (pts) with metastatic high-tumor mutational burden (TMB-h, ≥ 10 mutations/megabase) solid tumors, agnostic of primary site, combined with clinical trials in melanoma reporting efficacy of immune checkpoint inhibitors (ICI) against BM, suggest a potential use of ICI for pts with TMB-h BCBM. Results of the TAPUR study supported modest therapeutic benefit of pembro for 28 pts with metastatic BC selected for TMB-h, with median OS of 30.6 weeks, but did not include pts with active BCBM. TMB-h is uncommon in BC, and further genomic signatures remain to be elucidated to identify pts with BCBM responsive to ICI. We present a remarkable case of a pt with Lynch Syndrome (LS) due to a germline PMS2 mutation, who developed TMB-h, mismatch repair (MMR)-deficient TN BCBM, and has maintained stable disease for over 6 years on pembro monotherapy. Case description A 62-y.o. woman underwent screening mammography that identified a right breast mass. Pt has a family history of a mother with uterine and pancreatic cancer, and father with bladder cancer. Biopsy confirmed invasive ductal carcinoma (IDC), grade 1 (G1), ER/PR-positive, HER2 score 0. She underwent partial mastectomy, axillary dissection, radiation, and received adjuvant anastrozole. Three years later, while still on anastrozole, she presented with a 6 cm right breast mass. Mastectomy disclosed G3, ER/PR-negative, HER2-positive (3+, Her2:CEP17 ratio 5.6) IDC. She received adjuvant chemotherapy (AC-T) and 1 year of trastuzumab. Seven years later, pt presented with headaches and word finding difficulties. MRI identified a 3.6 cm frontal mass, which biopsy revealed as TN BCBM. Systemic imaging ruled out distant metastases. Pt proceeded with SRT and exemestane (despite receptor staining ER- in case of a possible false negative result). Despite radiotherapy, pt had BCBM progression within the same year with the largest mass diameter grown to 4.8 cm. Resection (followed by SRT) identified the dominant histology as G3 TNBC. Following transition of care to our institution, germline testing revealed a pathogenic mutation in PMS2 (c943C >T). Tumor sequencing of the resected brain metastasis showed TMB of 48 and MMR deficiency. Therefore, systemic therapy with pembro monotherapy was initiated and maintained with good tolerability. Two years later, concern for progression from rising tumor markers led to addition of concurrent carboplatin/gemcitabine for 5 cycles. Imaging and tumor markers stabilized, and pt returned to pembro monotherapy. Today, 3 years later, and over 6.5 years after initial TN BCBM diagnosis, pt continues to have stable disease on pembro with an excellent performance status (ECOG 0) and no evidence of intracranial or extracranial progression. Discussion We document an exceptional case of prolonged benefit to pembro in a pt with TMB-h PMS2-mutated MMR-deficient TN BCBM. This case highlights two major pragmatic points to clinical practice; (i) the significance of germline testing in all pts with metastatic BC, and (ii) the impact of molecular testing of tumor tissue to identify rare alterations which may have dramatic effects on pt outcomes. Altogether, this case is a remarkable addition to growing evidence that TMB could be a biomarker for predicting response to ICI therapy and provides an example of ICI efficacy in the setting of BCBM. Further research on additional genomic, clinical, and pathologic features associated with ICI responsiveness is warranted for greater precision in BCBM management. Citation Format: Jaeyoon Cha, Albert Grinshpun, Lauren Buckley, Brian Alexander, Sara Tolaney, Nancy Lin. Exceptional long-term disease control on pembrolizumab monotherapy in a patient with TMB-high PMS2-mutated MMR-deficient triple negative breast cancer brain metastasis [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 PO2-20-10.

Abstract PO5-25-04: Predictive value of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in patients with triple negative breast cancer treated with pembrolizumab

Abstract Background: Immune checkpoint inhibitors (ICIs) offer new treatment possibilities for women with triple-negative breast cancer (TNBC) – one of the most challenging breast cancer subtypes. The PD-1 inhibitor pembrolizumab (pembro; Keytruda®) is approved in metastatic TNBC (mTNBC) patients with PD-L1(+) tumors, and for neoadjuvant treatment (NAT) in stage II/III TNBC [1, 2]. Residual cancer burden (RCB) after NAT is highly prognostic, with pathologic complete response (pCR, RCB 0) anticipating long-term survival [3]. In mTNBC, pembro plus chemotherapy in the 1st-line improves progression free survival (PFS), but durable responses are rare. Optimizing ICI use in TNBC thus remains an unmet need, and defining easily assessable markers of response is crucial. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are peripheral blood surrogates of tumor inflammation and have prognostic and predictive value in TNBC [4-8]. Elevated NLR (≥ 5) and PLR (≥ 200) correlate with worse outcomes upon ICIs in melanoma and non-small-cell lung cancer [9, 11-14]; however, this has not been studied in breast cancer [9, 10]. We evaluated the relationship of baseline NLR and PLR with pembro responses in TNBC patients. Methods: We retrospectively reviewed data from TNBC patients who completed pembro between 10/2/20 - 6/1/23 at Weill Cornell. Patients on NAT who did not complete treatment were excluded. RCB score (pCR/0, 1, 2, 3) was calculated from surgical resection pathology reports using the MD Anderson RCB Calculator [15, 16]. Baseline laboratory data were obtained from clinical records. Associations between NLR and PLR with RCB levels were examined using the non-parametric Kruskal-Wallis test (if >2 levels), the Wilcoxon rank sum test (if 2 levels), or the Spearman’s rank correlation. NLR and PLR were also correlated with PFS (measured from pembro start date to date of progression) in metastatic patients. PFS data for metastatic patients without interval imaging since pembro initiation were censored at the date of data analysis, and PFS was not calculated for patients who received only 1 cycle of pembro. Results: We identified 63 eligible patients: 24 were excluded due to lack of TNBC diagnosis (n=20), or because they only received adjuvant pembro (n=4). Of the 39 remaining patients, 5 did not complete NAT and 2 had missing data, leaving 32 evaluable patients (17 in the NAT cohort and 15 in the mTNBC cohort). Overall, the median age was 51 years, and 16% were Hispanic, 11% Asian, 57% non-Hispanic, 24% Black, and 65% Non-Black. Neoadjuvant cohort: The pCR rate was 30%. Patients with both NLR ≥ 5 and PLR ≥ 200, had a pCR rate of 0%; in patients with NLR < 5 or PLR < 200, pCR rate was 43%. Median NLR in pCR vs. non-pCR groups was 1.91 [IQR: 1.72- 2.73] vs. 2.44 [IQR: 1.97- 5.24] (p=0.3), with trends towards significance when NLR was compared between RCB levels >1 (2.67; IQR: 2.05, 6.49) vs. RCB levels ≤1 (1.91; IQR: 1.63, 2.58) (p=0.14). Mean PLR was higher in patients with RCB 2-3 (409) compared to those with pCR or RCB 1 (167) (p=0.146). Metastatic cohort: The overall mean PFS was 7.8 months. Visceral metastases were seen in 80% of patients (17% liver, 33% brain). In patients with brain mets, baseline NLR and PLR were higher than in the overall cohort (NLR, 4.86 vs. 2.78; PLR, 429 vs. 186). Conclusions: Our study is the first to evaluate NLR and PLR as response biomarkers in TNBC patients receiving pembro and is the first report of our real-world data of TNBC patients on pembro. In our neoadjuvant cohort, higher baseline NLR and PLR correlated with higher RCB levels, with a trend towards statistical significance. Further investigation and correlation of NLR and PLR with tumor microenvironment features will help to clarify these relationships. Citation Format: Ashley Schreier, Roberta Zappasodi, Inna Serganova, Laura Munoz Arcos, Xi Kathy Zhou, Massimo Cristofanilli, Eleni Andreopolu. Predictive value of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in patients with triple negative breast cancer treated with pembrolizumab [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 PO5-25-04.

Unanticipated pathological clearance in two cases of clinical T4b dMMR/MSI-h advanced colorectal cancer: the potential of immune checkpoint inhibitors despite positive positron-emission tomography results.

The standard treatment for colorectal cancer consists of surgery and chemotherapy, which can be combined to improve outcomes. Immune checkpoint inhibitors (ICI) are a significant advancement in the standard treatment of metastatic, unresectable colorectal cancer with deficient mismatch repair (dMMR). However, limited data are available about the use of ICI in the neoadjuvant and conversion settings. Here, we present two cases treated with ICI. Case 1: A 75-year-old male with a large, borderline resectable rectal cancer diagnosed as cT4bN1bM0 who underwent neoadjuvant chemotherapy, followed by combination ICI consisting of ipilimumab and nivolumab. After four courses of ICI, the tumor significantly shrank, but positron emission tomography still showed a positive result and R0 resection was performed. Pathological analysis revealed no residual cancer cells. The patient has been monitored without adjuvant chemotherapy, and no recurrences have occurred after one year. Case 2: A 60-year-old male with locally advanced sigmoid colon cancer who received neoadjuvant treatment with pembrolizumab. The tumor partially shrank after three courses, and continued pembrolizumab monotherapy resulted in further tumor shrinkage which still showed positive positron emission tomography. Curative sigmoidectomy with partial resection of the ileum and bladder was performed, and the pathological outcome was pCR. There was no viable tumor in the specimen. The patient has been monitored without adjuvant chemotherapy for six months, and no recurrence has been observed. The present study reports two cases, including a large, borderline resectable rectal cancer after failure of chemotherapy followed by combination treatment with nivolumab and ipilimumab and one case of sigmoid colon cancer after pembrolizumab treatment, which resulted in pathological complete response. However, it remains unknown whether ICI therapy can replace surgery or diminish the optimal extent of resection, or whether adjuvant chemotherapy is needed after surgery in the case of achieving pCR after ICI therapy. Overall, this case report suggests that ICI before colorectal surgery can be effective and potentially a 'watch-and-wait" strategy could be used for cases in which ICI is effective.

Artificial neural network identified a 20-gene panel in predicting immunotherapy response and survival benefits after anti-PD1/PD-L1 treatment in glioblastoma patients.

Immune checkpoint inhibitors (ICIs) are a promising immunotherapy approach, but glioblastoma clinical trials have not yielded satisfactory results. To screen glioblastoma patients who may benefit from immunotherapy. Eighty-one patients receiving anti-PD1/PD-L1 treatment from a large-scale clinical trial and 364 patients without immunotherapy from The Cancer Genome Atlas (TCGA) were included. Patients in the ICI-treated cohort were divided into responders and nonresponders according to overall survival (OS), and the most critical responder-relevant features were screened using random forest (RF). We constructed an artificial neural network (ANN) model and verified its predictive value with immunotherapy response and OS. We defined two groups of ICI-treated glioblastoma patients with large differences in survival benefits as nonresponders (OS ≤6 months, n = 18) and responders (OS ≥17 months, n = 8). No differentially mutated genes were observed between responders and nonresponders. We performed RF analysis to select the most critical responder-relevant features and developed an ANN with 20 input variables, five hidden neurons and one output neuron. Receiver operating characteristic analysis and the DeLong test demonstrated that the ANN had the best performance in predicting responders, with an AUC of 0.97. Survival analysis indicated that ANN-predicted responders had significantly better OS rates than nonresponders. The 20-gene panel developed by the ANN could be a promising biomarker for predicting immunotherapy response and prognostic benefits in ICI-treated GBM patients and may guide oncologists to accurately select potential responders for the preferential use of ICIs.

Molecular profiling of a bladder cancer with very high tumour mutational burden

The increasing incidence of urothelial bladder cancer is a notable global concern, as evidenced by the epidemiological data in terms of frequency, distribution, as well as mortality rates. Although numerous molecular alterations have been linked to the occurrence and progression of bladder cancer, currently there is a limited knowledge on the molecular signature able of accurately predicting clinical outcomes. In this report, we present a case of a pT3b high-grade infiltrating urothelial carcinoma with areas of squamous differentiation characterized by very high tumor mutational burden (TMB), with up-regulations of immune checkpoints. The high TMB, along with elevated expressions of PD-L1, PD-L2, and PD1, underscores the rationale for developing a personalized immunotherapy focused on the use of immune-checkpoint inhibitors. Additionally, molecular analysis revealed somatic mutations in several other cancer-related genes, including TP53, TP63 and NOTCH3. Mutations of TP53 and TP63 genes provide mechanistic insights on the molecular mechanisms underlying disease development and progression. Notably, the above-mentioned mutations and the elevated hypoxia score make the targeting of p53 and/or hypoxia related pathways a plausible personalized medicine option for this bladder cancer, particularly in combination with immunotherapy. Our data suggest a requirement for molecular profiling in bladder cancer to possibly select appropriate immune-checkpoint therapy.

Non–small cell lung cancer and immune checkpoint inhibitor therapy: does non-alcoholic fatty liver disease have an effect?

BackgroundImmunotherapy based on the application of immune checkpoint inhibitors (ICIs) is one of the standard treatments for advanced non-small cell lung cancer (NSCLC). Non-alcoholic fatty liver Disease (NAFLD) has demonstrated predictive value for response to immunotherapy in non-lung cancer types. Our study investigated the effect of NAFLD on the efficacy of real-life use of ICIs for patients with stage III / IV NSCLC.MethodsThe clinical and imaging data of patients with stage III / IV NSCLC who were first admitted to Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from March 2020 to July 2022 were retrospectively collected to ensure that they underwent at least one CT scan before treatment. A total of 479 patients were divided into the NAFLD group (Liver/Spleen density ratio ≤ 1) and the non-NAFLD group (Liver/Spleen density ratio > 1) by measuring the baseline liver and spleen CT value. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) of the patients were obtained.ResultsA total of 118 patients with NAFLD and 361 patients without NAFLD were included in the study. Patients with NAFLD tended to have higher BMI and higher total bilirubin compared to patients without NAFLD. The median duration of follow-up in the study was 22 m (IQR, 17–29 m). Both of 2 groups had a higher DCR (94% vs. 92%, p = 0.199) and ORR (38.1% vs. 44.9%, p = 0.452) respectively. There was no difference in efficacy between the two groups. In univariate analysis, NAFLD had no significant effect on PFS (p = 0.785) and OS (p = 0.851). Surprisingly, the presence of hypertension was observed to be associated with a higher OS (HR 1.471 95%CI 1.018–2.127, p = 0.040). Besides, based on multivariate analysis, lactic dehydrogenase was associated with PFS (HR 1.001 95%CI 1.000,1.002, p = 0.037) and OS (HR 1.002, 95%CI 1.001–1.003, p < 0.001).ConclusionsAmong patients with NSCLC, NAFLD did not result in changes in survival or disease progression after immune checkpoint inhibitor therapy.

A Multicenter Study on the Challenges and Real-World Utilization of Immune Checkpoint Inhibitors in Resource-Constrained Settings: Insights and Implications from India

Using immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, but access and affordability remain significant challenges, particularly in resource-constrained settings. This multicenter study evaluated the utilization, outcomes, and challenges associated with ICIs in India. Data from multiple centers involving patients treated between January 2018 and December 2021 were retrospectively collected. Patient demographics, treatment indications, biomarker testing, financial coverage, toxicity, treatment discontinuation, clinical benefit, progression-free survival (PFS), and overall survival (OS) were analyzed. Ninety-one patients were analyzed; lung cancer (39.6%) and renal cancer (11%) were the main indications for ICI use. Programmed death ligand 1 expression was tested in 40.7% and tumor mutational burden in 3.3%. Financial constraints influenced 41.8% of patients with out-of-pocket expenses. Treatment discontinuation due to financial constraints occurred in 17.6%, with 50% showing ongoing responses. The median number of cycles was 4; the median PFS was 4.6 months, and the median OS was 15.4 months. The lung cancer cohort had a median PFS of 5.7 months and a 1-year OS of 57.6%. Limited biomarker testing and 6.6% grade ¾ toxicities were observed. This study revealed challenges in ICI utilization in resource-constrained settings driven by financial constraints. Compared with prior studies, improved outcomes reflect better patient selection and evolving understanding of ICI use. However, in the absence of biosimilars, cost remains a significant barrier. Solutions to increase access include using lower doses, which may be as effective.

Effect of immune checkpoint inhibitors at different treatment time periods on prognosis of patients with extensive-stage small-cell lung cancer.

The application of immune checkpoint inhibitors (ICIs) in treating patients with extensive-stage small-cell lung cancer (ES-SCLC) has brought us new hope, but the real-world outcome is relatively lacking. Our aim was to investigate the clinical use, efficacy, and survival benefit of ICIs in ES-SCLC from real-world data analysis. A retrospective analysis of ES-SCLC patients was conducted between 2012 and 2022. Progression-free survival (PFS) and overall survival (OS) were assessed between groups to evaluate the value of ICIs at different lines of treatment. PFS1 was defined as the duration from initial therapy to disease progression or death. PFS2 was defined as the duration from the first disease progression to the second disease progression or death. One hundred and eighty patients with ES-SCLC were included. We performed landmark analysis, which showed that compared to the second-line and subsequent-lines ICIs-combined therapy group (2SL-ICIs) and non-ICIs group, the first-line ICIs-combined therapy group (1L-ICIs) prolonged OS and PFS1. There was a trend toward prolonged OS in the 2SL-ICIs group than in the non-ICIs group, but the significance threshold was not met (median OS 11.94months vs. 11.10months, P = 0.14). A longer PFS2 was present in the 2SL-ICIs group than in the non-ICIs group (median PFS2 4.13months vs. 2.60months, P < 0.001). First-line ICIs plus chemotherapy should be applied in clinical practice. If patients did not use ICIs plus chemotherapy in first-line therapy, the use of ICIs in the second line or subsequent lines of treatment could prolong PFS2.

Immune Checkpoint Inhibitor Colitis, a Rising Issue in Targeted Cancer Therapy Era: A Literature Review.

Research advances in the oncology treatment field have led to the widespread use of immunotherapy. The usage of immune checkpoint inhibitor (ICI) has improved the survival of cancer patients with metastases. This has also led to the rapidly expanding indications for ICI use. However, ICI usage may lead to toxicity, which may be immune-related, in different organ-specific targets. The immune-related adverse events (irAEs) of ICI may lead to increased morbidity, decreased quality of life, and early termination of ICI. The clinical manifestations of irAEs in the gastrointestinal system are variable, ranging from self-limited to life-threatening or fatal events. In this review article, we would like to focus on discussing ICI-induced colitis, which is one of the most common ICI irAEs in the gastrointestinal tract.

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations.

The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.

Off-label prescribing of immune checkpoint inhibitor therapy at a single pediatric cancer center.

Immune checkpoint inhibitors (ICI) have improved outcomes in a variety of adult cancers and are prescribed with increasing frequency across oncology. However, patterns of off-label use of ICI in pediatrics remain unclear. This is a single-institution, retrospective cohort study evaluating off-label ICI use in pediatric and young adult patients with cancer treated at our institution from 2014 to 2022. Response was based on clinician assessment derived from clinical records. Immune-related adverse events (iRAEs) were classified according to CTCAE v5.0. We identified 50 unique patients treated with off-label ICI (28 with solid tumors, 20 with central nervous system (CNS) tumors, 2 with hematologic malignancies). At time of ICI initiation, only five patients (10%) had localized disease, and all but one patient was treated in the relapsed/refractory setting. All patients were treated with the FDA-approved weight-based dosing recommendations. Overall, there was disease control in 21 patients (42%), with best response including one complete response (melanoma), two partial responses (high-grade glioma, CNS nongerminomatous germ cell tumor), and 18 patients with stable disease. Forty-four patients (88%) eventually experienced disease progression. Among 22 patients (44%) experiencing iRAEs, 10 (20%) had a grade ≥3 irAE, 12 (24%) required corticosteroids, and 14 (28%) required ICI discontinuation. irAE occurrence was associated with significantly improved progression-free survival (HR 0.35; 95% CI: 0.18 to 0.68; p = 0.002) and overall survival (HR 0.33; 95% CI: 0.17 to 0.66; p = 0.002). At our institution, ICI was most commonly prescribed in the relapsed/refractory setting to patients with metastatic disease. The treatment was generally well-tolerated in the pediatric population. The overall response rate was low, and the majority of patients eventually experienced disease progression. A few patients, however, had durable treatment responses. Further studies are needed to identify which pediatric patients are most likely to benefit from ICI.

Predictors of Immunotherapy Efficacy in Metastatic Non-Small Cell Lung Cancer: Lung Immune Prognostic Index and Immune-Related Toxicity.

Immune checkpoint inhibitors (ICIs) have been proposed as the standard first-line and subsequent treatment for metastatic non-small cell lung cancer (NSCLC). This study analyzed whether patients with good lung immune prognostic index (LIPI) have a better response to ICIs and the relationship between immune-related adverse events (irAEs) and response in clinical practice. This was an observational, retrospective, single-center study. Patients with stage IV NSCLC between 2016 and 2021 were included in the study. Toxicity was assessed according to The Common Terminology Criteria for Adverse Events. Response assessment was performed according to RECIST 2.0 and immuno-related criteria. Descriptive and survival analyses were conducted. Degree of toxicity and response to treatment (based on treatment and histology) were assessed. LIPI and response were assessed. LIPI included dNLR (absolute neutrophil count/(white blood cell count - absolute neutrophil count)) ≥ 3 and lactate dehydrogenase (LDH) greater than the upper limit of normal. Patients were stratified into good (G), intermediate (I), and poor (P) prognostic groups. A total of 168 patients were included (130 men and 38 women, mean age 64.3 years). ICI use in the first- or second-line treatment was 65% and 35%, respectively. Fifteen (9%) patients showed complete response (CR), 50 (30%) showed partial response (PR), 39 (22%) had stable disease (SD), 45 (28%) had progressive disease (PD), and 19 (11%) were not evaluated (NE). Patients with good prognostic LIPI (dNLR < 3 and normal LDH levels) showed a better response. Progression-free survival (PFS) was 19 months in G, 6 months in I, and 2 months in P. Overall survival (OS) was 27 months in G, 8 months in I, and 3 months in P. One hundred fourteen patients died (56% G, 76% I, 93% P). Patients with adenocarcinoma were 116 (77 with irAEs G1-4 (13 CR, 31 PR, 21 SD, eight PD, and four NE)), and without were 39 (three PR, six SD, 21 PD, and nine NE). Fifty-two patients had squamous carcinoma (27 with irAEs G1-4 (two CR, 12 PR, nine SD, and four PD)), and 25 did not (four PR, three SD, 12 PD, and six NE)). IrAEs appearance was observed in longer PFS (19 vs. 2 months) and OS (27 vs. 4 months; P < 0.0001). LIPI was a positive predictor of response to ICI. The presence of irAEs is associated with a better immune response. In contrast, the absence of toxicity predicted a worse prognosis.

Immune Checkpoint Inhibitor Use During Pregnancy and Outcomes in Pregnant Individuals and Newborns

With the widespread use of immune checkpoint inhibitors (ICIs), concerns about their pregnancy outcomes through maternal exposure have emerged, and clinical comparative data are lacking. To assess the risk of pregnancy-, fetal-, and/or newborn-related adverse outcomes associated with exposure to ICIs compared with exposure to other anticancer agents. In this cohort study, all reports mentioning a pregnancy-related condition and an antineoplastic agent (Anatomical Therapeutic Chemical classification group L01) used for a cancer indication registered in the World Health Organization international pharmacovigilance database VigiBase up to June 26, 2022, were extracted. Anticancer agents, including ICIs, used during pregnancy for a cancer indication. Immune checkpoint inhibitors included blockers of programmed cell death 1 (PD1) or its ligand (PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA4). The main outcome was the reporting odds ratio (ROR) for maternal, fetal, or newborn complications in patients treated with ICIs vs any other anticancer drug. Adverse events, categorized into 45 individual maternofetal adverse outcomes, were directly mapped to Medical Dictionary for Regulatory Activities preferred terms in VigiBase. A total of 3558 reports (ICI: 91 [2.6%]; other anticancer drugs: 3467 [97.4%]) were included in the analysis. In the ICI group, most reports were from the US (60 [65.9%]), and the mean (SD) patient age was 28.9 (10.2) years; in 24 of 55 reports with data on cancer type (43.6%), patients were treated for melanoma. The molecules involved in the ICI group were anti-PD1 (58 reports [63.7%]), anti-PD1 plus anti-CTLA4 (15 [16.5%]), anti-CTLA4 (13 [14.3%]), anti-PD-L1 (4 [4.4%]), and anti-PD1 plus anti-lymphocyte activation gene 3 (1 [1.1%]). An ICI was used in combination with a non-ICI anticancer agent in 10 participants (11.0%). Compared with other anticancer drugs, none of the 45 adverse outcomes identified were overreported in the group exposed to ICIs. However, preterm birth was significantly overreported for the anti-PD1 plus anti-CTLA4 combination compared with other anticancer drugs (12 of 15 [80.0%] vs 793 of 3452 [23.0%]; ROR, 13.87; 95% CI, 3.90-49.28; P < .001) but not for anti-PD-L1 or anti-CTLA4 monotherapy. Three reports of possibly immune-related maternofetal events were identified: 1 case of maternal antiphospholipid syndrome leading to spontaneous abortion, 1 case of pneumonitis leading to neonatal respiratory distress syndrome and death, and 1 case of transient congenital hypothyroidism. In this cohort study of 91 individuals exposed to ICIs during pregnancy, ICI exposure was not associated with overreporting of specific adverse pregnancy, fetal, and/or newborn outcomes compared with other anticancer treatments. However, due to possible rare immune-related neonatal adverse events, ICI use in pregnant women should be avoided when possible, especially the anti-PD1 plus anti-CTLA4 combination.

Clinical outcomes after use of checkpoint inhibitor immunotherapies in people with multiple sclerosis.

Immune checkpoint inhibitors (ICIs) represent a novel class of agents approved for the treatment of several cancers and progressive multifocal leukoencephalopathy (PML). However, due to the risk of autoimmune side effects, their use in people with autoimmune diseases such as multiple sclerosis (MS) has been limited. To characterize outcomes in a cohort of adults with MS who received ICIs. A single-center retrospective review of medical record data was performed for people with MS treated with ICIs. Seven people with MS were identified, with a mean (SD) age at ICI use of 55.4 (13.7) years and a mean MS duration of 18.2 (12.2) years. Six were treated for cancer; 1 was treated for PML. After mean (SD) follow-up of 1.76 (2.15) years after ICI, outcomes are: no evidence of disease (2), residual metastatic disease (1), death due to cancer (1), death due to PML (1), and lost to follow-up (2). Notably, 0 out of 7 patients experienced an MS relapse; two out of six had new asymptomatic demyelinating magnetic resonance imaging lesions. In the three patients with expanded disability status scale (EDSS) scores at baseline and follow-up, EDSS remained stable (mean delta 0.13). In this cohort, no people with MS experienced clinical relapses and one-third experienced asymptomatic radiological activity following ICI treatment.

Cost-effectiveness of immune checkpoint inhibitors in treating metastatic urothelial cancer.

Objectives: Immune checkpoint inhibitor (ICI) is an important treatment option for metastatic urothelial carcinoma (mUC) patients. A lot of clinical evidence proved the survival benefits of ICI, but cost-effectiveness of the treatment remains unclear. This study evaluates the cost-effectiveness of the ICIs treatment in different sequences among mUC patients. Methods: We retrospectively analyzed mUC patients who had been treated at our hospital between January 2016 and December 2020. These patients received chemotherapy with or without ICI treatment (Pembrolizumab, Atezolizumab, Nivolumab, Durvalumab, or Avelumab). The patients were divided into three different groups: receiving chemotherapy alone, receiving a combination of first-line ICI and chemotherapy (ICI combination therapy), and receiving chemotherapy as the first-line treatment followed by second-line ICI therapy (Subsequent ICI therapy). The primary endpoint was cost per life day, while lifetime medical costs and overall survival were also evaluated. Results: The 74 enrolled patients had a median age of 67.0 years, with 62.2% being male. Of these patients, 23 had received chemotherapy only, while the remaining patients had received combined therapy with ICI in either first-line or as subsequent agents (37 patients had ever received atezolizumab, 18 pembrolizumab, 1 Durvalumab, 1 Nivolumab, and 1 Avelumab separately.). Fifty-five patients (74.3%, 55/74) received cisplatin amongst all the patients who underwent chemotherapy. Median overall survival was 27.5months (95% CI, 5.2-49.9) in the first-line ICI combination therapy group, and 8.9months (95% CI, 7.1-10.8) in the chemotherapy only. Median overall survival for the subsequent ICI therapy group was not reached. The median lifetime cost after metastatic UC diagnosis was USD 31,221. The subsequent ICI therapy group had significantly higher costs when compared with the ICI combination therapy group (155.8 USD per day, [IQR 99.0 to 220.5] v 97.8 USD per day, [IQR 60.8 to 159.19], p = 0.026). Higher insurance reimbursement expenses for the subsequent ICI therapy group were observed when compared with the ICI combination therapy group. Conclusion: Our real-world data suggests that first line use of ICI combined with chemotherapy demonstrates better cost-effectiveness and similar survival outcomes for mUC patients, when compared with subsequent ICI therapy after chemotherapy.

Side Effects and Research Progress of Immune Checkpoint Inhibitors

Immune checkpoint inhibitor (ICI) is a new type of tumor treatment drug, also known as immunotherapy drug. They target "checkpoint" molecules in the body's immune system that prevent immune cells from attacking cancer cells. They target "checkpoint" molecules in the body's immune system that prevent immune cells from attacking cancer cells. The use of immune checkpoint inhibitors can help control or treat certain types of cancer by promoting the restoration of inactivated immune cells and enhancing the immune system's ability to attack. -This article focuses on skin reactions, immune pneumonitis, and adverse reactions in the thyroid and digestive tract. Through the analysis of recent relevant research, this question summarizes several different side effects, their causes and treatments. Although there are many treatments to deal with the side effects of this drug, it is important to note that the side effects of this drug are not always well understood. There are many treatments to deal with the related side effects, these side effects are still a barrier to the current use of ICIs. Future development directions should focus more on the development of ICIs. directions should focus more on the development of new targets, optimization of drug pharmacokinetics, and alleviation of side effects caused by ICIs.

Abstract 912: CheckpointPx, an interpretable radiology AI tool, predicts checkpoint blockade benefit independent of PDL1 status in non-small cell lung cancers (NSCLC): A multi-institutional validation study

Abstract Background: Immune Checkpoint Inhibitors (ICIs) are a cornerstone in the treatment of cancers such as Non-Small Cell Lung Cancer (NSCLC). Despite the standard use of biomarkers such as PD-L1 expression for selecting ICI regimens, recent studies suggest missed opportunities for benefit in PD-L1 low/negative patients. Therefore, there is an urgent need for new biomarker strategies capable of guiding the use of ICIs in NSCLC. We introduce and validate an AI-powered radiology tool for ICI patient selection that provides interpretable predictions by quantifying aspects of tumor biology on baseline CT scans directly associated with ICI efficacy, such as tumor heterogeneity and twistedness of the tumor-associated vasculature. Methods: We analyzed CT scans of 439 patients treated with ICI at 4 institutions (D1-D4) using the Picture Health Px platform. Experienced radiologists and physicians across institutions delineated target lesions on baseline CT scans. A deep learning model was used to segment pulmonary vessels. CheckpointPx v1.11, an interpretable neural network incorporating quantitative features extracted from within the tumor and its vasculature, was trained to predict ICI response (defined as disease control per RECIST best overall response) on n=247 patients (D1-D3). It was assessed with respect to response and progression free-survival (PFS) on 192 patients (D2-D4), with D4 (n=105) being an external validation set. CheckpointPx was also evaluated within PDL1 subsets among testing set patients where available (n=138). Results: The cohort was predominantly late stage (Stage 3/4) (&amp;gt;85%) and was mixed with respect to ICI line of treatment (1st-4th). 122 of 247 (49%) and 119 of 192 (62%) were responders in training and test cohorts respectively. CheckpointPx included 16 features, such as entropy-based heterogeneity and quantitative vessel tortuosity (twistedness). The model predicted response to ICI with an AUC=0.65 on the test set. The CheckpointPx High Risk group significantly stratified patients by PFS (HR=1.67 [1.22-2.28], p=0.001). This separation remained significant within the subset of PDL1-negative (HR=2.71 [1.35-5.44], p=0.005) and PDL1-positive patients (HR=2.05 [1.22-3.46], p=0.007). Conclusions: From baseline radiology, CheckpointPx was shown to strongly predict ICI outcomes across multiple institutions, NSCLC stages, and lines of ICI. Furthermore, the tool stratified patients by ICI benefit within both PDL1-positive and negative subsets - suggesting the potential of CheckpointPx to address critical gaps in the NSCLC biomarker landscape. CheckpointPx is driven by interpretable imaging biomarkers, and thus its predictions are tied to specific and quantifiable phenotypic attributes of the tumor and its microenvironment. Citation Format: Amogh Hiremath, Seyoung Lee, Jeeyeon Lee, Peter Haseok Kim, Kai Zhang, Salie Lee, Monica Yadav, Maria Jose Aguilera Chuchuca, Taegyu Um, Myungwoo Nam, Liam Il-Young Chung, Hye Sung Kim, Jisang Yu, Trie Arni Djunadi, Leeseul Kim, Youjin Oh, Sungmi Yoon, Zunairah Shah, Yuchan Kim, Ilene Hong, Grace Kang, Jessica Jang, Amy Cho, Soowon Lee, Cecilia Nam, Timothy Hong, Yury S. Velichko, Amit Gupta, Vamsidhar Velcheti, Anant Madabhushi, Nathaniel Braman, Young Kwang Chae. CheckpointPx, an interpretable radiology AI tool, predicts checkpoint blockade benefit independent of PDL1 status in non-small cell lung cancers (NSCLC): A multi-institutional validation study [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 912.

Abstract 700: Impact of heterogeneity for mismatch repair activity on colon tumor development and therapeutic response

Abstract Background: Colorectal cancers (CRC) that are deficient for DNA mismatch repair (dMMR) proteins have high levels of genetic instability and consequently high mutational burden, creating numerous neoantigens that can elicit an immune response. Therefore, dMMR CRC are the best candidates for immune checkpoint inhibition (ICI) compared to proficient DNA mismatch repair (pMMR) CRC. Early clinical trials revealed that only 30-55% metastatic dMMR CRC responded to ICI. Recent studies utilizing allograft models have demonstrated that tumor immune landscape can be primed with radiopharmaceutical therapy (RPT). Although early results have been quite promising, allograft models often fail to accurately predict efficacy for many reasons, but most often are due to a lack of heterogeneity. Methods: To better understand how heterogenous MMR expression impacts tumor development and response to ICI alone or in combination with RPT, we developed a new mouse model that develops three tumor types: (1) homotypic dMMR tumors that express green fluorescent protein, (2) homotypic pMMR tumors that express red fluorescent protein, and (3) heterotypic tumors with a mixture of dMMR and pMMR cells. Surveillance bright field and fluorescent colonoscopies allow us to assess treatment response by measuring tumor size and proportion of dMMR and pMMR tumor cells in real-time. These outcomes are verified through ex vivo imaging and histological analysis. Results: Tumor response to anti-PD-L1 ICI was dependent on MMR status. Homotypic dMMR tumors exhibited the strongest response: significantly smaller in treated mice than controls, exhibited areas of vascular congestion and increased CD8+ cytotoxic T-cells infiltration. Response of heterotypic MMR tumors varied depending on percentage of dMMR cells; tumors with a high percentage of dMMR cells remained small, whereas tumors with a low percentage of dMMR had an outgrowth of pMMR cells. Treated and untreated homotypic pMMR tumors were indistinguishable. To enhance the response of all three tumor types, mice were treated with dual ICI treatment, anti-PD-L1 and anti-CTLA-4, or RPT. Animals administered the tri-therapy (dual ICI + RPT) survived significantly longer with fewer tumors than animals treated with either dual ICI or RPT alone. Conclusions: Our innovative mouse model allows for the highly detailed characterization of tumor response to therapies. Simplistic allograft models may not adequately account for the dynamic effects that neighboring cell death may have on radio-resistant cells, on tumor vascular perfusion and oxygenation, or on tumor immune infiltration and adaptive immune recognition of remaining cells. We begin to fill these critical gaps in knowledge and therefore the results from our studies will help guide the translation and integrated use of ICIs and RPTs in clinic. Citation Format: Santina M. Snow, Dawn Albrecht, Paul A. Clark, Caroline P. Kerr, Joseph J. Grudzinski, Justin J. Jeffery, Hansel Comas Rojas, Reinier Hernandez, Kristina A. Matkowskyj, Jamey P. Weichert, Zachary S. Morris, Richard B. Halberg. Impact of heterogeneity for mismatch repair activity on colon tumor development and therapeutic response [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 700.