Complete Response Patients Research Articles

Fecal Microbiome Composition Correlates with Pathologic Complete Response in Patients with Operable Esophageal Cancer Treated with Combined Chemoradiotherapy and Immunotherapy.

Background: Preclinical and clinical data indicate that chemoradiotherapy (CRT) in combination with checkpoint inhibitors may prime an anti-tumor immunological response in esophageal cancer. However, responses to neoadjuvant therapy can vary widely and the key biomarkers to determine response remain poorly understood. The fecal microbiome is a novel and potentially modifiable biomarker of immunotherapy response, and both fecal and tumor microbes have been found to associate with outcomes in esophageal cancer. Methods: Fecal and tumor samples were collected from patients with stage II-III resectable esophageal or gastroesophageal junction carcinoma treated with neoadjuvant immune checkpoint inhibitors (ICIs) plus CRT prior to surgical resection. Microbiome profiles were analyzed by 16S rRNA amplicon sequencing and taxonomic data were integrated with fecal metabolite analysis to assess microbial function. Results: The fecal microbiome of patients with pathological complete response (PCR) grouped in distinct clusters compared to patients with residual viable tumor (RVT) by Bray-Curtis diversity metric. Integrated taxonomic and metabolomic analysis of fecal samples identified a sphingolipid and primary bile acid as enriched in the PCR, the levels of which correlated with several bacterial species: Roseburis inulinivorans, Ruminococcus callidus, and Fusicantenibacter saccharivorans. Analysis of the tumor microbiome profiles identified several bacterial genera previously associated with esophageal tumors, including Streptococcus and Veillonella. Conclusions: These results further characterize the fecal and tumor microbiome of patients with operable esophageal cancer and identify specific microbes and metabolites that may help elucidate how microbes contribute to tumor response with neoadjuvant CRT combined with ICI.

Diagnostic performance of TILs-US score and LPBC in biopsy specimens for predicting pathological complete response in patients with breast cancer.

Tumor-infiltrating lymphocytes-ultrasonography (TILs-US) score is used to predict lymphocyte-predominant breast cancer (LPBC) in surgical specimens. We aimed to compare diagnostic performance of TILs-US score for predicting pathological complete response (pCR) with that of LPBC in biopsy specimens. TILs ≥ 50% in biopsy specimens was defined as biopsy-LPBC, and TILs-US score ≥ 4 was categorized as TILs-US score-high. Basic nomogram for pCR was developed using stepwise logistic regression based on the smallest Akaike Information Criterion, and biopsy-LPBC and TILs-US score nomograms were developed by integrating biopsy-LPBC or TILs-US scores into a basic nomogram. The diagnostic performance of the nomograms for pCR was compared using area under the curve (AUC), categorical net reclassification improvement (NRI), and integrated discrimination improvement (IDI). This retrospective study evaluated 118 patients with breast cancer, including 33 (28.0%) with biopsy-LPBC, 52 (44.1%) with TILs-US score-high, with 34 (28.8%) achieving pCR. The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and AUC for predicting pCR were 0.53, 0.82, 2.96, 0.57, and 0.68, respectively, for biopsy-LPBC, and 0.76, 0.69, 2.47, 0.34, and 0.73, respectively, for TILs-US score. The biopsy-LPBC nomogram showed significant improvements in categorical NRI (p = 0.023) and IDI (p = 0.007) but not in AUC (p = 0.25), compared with the basic nomogram. The TILs-US nomogram exhibited significant improvements in AUC (p = 0.039), categorical NRI (p = 0.010), and IDI (p < 0.001). The TILs-US score may serve as a novel marker for prediction of pCR in patients with breast cancer. An external validation study is warranted to confirm our findings.

WT1 Expression Is Associated with Poor Overall Survival after Azacytidine and DLI in a Cohort of Adult AML and MDS Patients.

Introduction: Post-transplant relapse of acute myeloid leukemia and myelodysplastic syndrome faces restricted effective salvage regimens. We retrospectively analyzed the use of Azacitidine-donor lymphocyte infusion (AZA/DLI) in this setting. Furthermore, data on bone marrow Wilms tumor gene 1 (WT1) expression were collected. Methods: A Cox proportional hazards model, an outcome-oriented approach for the lowest smoothed plot of the martingale residuals, was performed for the cut-point determination of the respective WT1 expression levels. Finally, a Cox proportional hazards model investigated the association of overall survival (OS) with predictors. Results: An overall response of 41.4% with a median duration of 11.9 months for stable disease and 19.5 months for complete response (CR) patients was achieved. The disease risk index (DRI) high-/very high-risk patients had a shorter OS of 4.4 months than intermediate-risk patients, with 14.5 months, p = 0.007. At transplant, WT1-overexpressing patients (>150 copies) had a shorter median OS of 5.3 months than low-WT1-expressing ones, with 13.5 months, p = 0.024. Furthermore, patients with ≤1000 WT1 copies at relapse had a significantly longer OS with 15.3 months than patients overexpressing WT1, with 4.4 months, p = 0.0002. Conclusions: DRI and WT1 expression associate significantly with OS after AZA/DLI. Hence, WT1 may represent an MRD marker, especially in CR patients at high risk.

263P Association between clinicopathological characteristics and pathological complete response in patients with triple negative breast cancer treated by neoadjuvant chemo-immunotherapy

263P Association between clinicopathological characteristics and pathological complete response in patients with triple negative breast cancer treated by neoadjuvant chemo-immunotherapy

Analysis of Factors Associated With Pathological Complete Response in Patients With HER2-Positive Breast Cancer Receiving Neoadjuvant Chemotherapy

PurposeThis study aimed to examine the impact of the level of HER2 overexpression on pathologic and clinical outcomes in HER2-positive breast cancer (BC) patients treated with neoadjuvant therapy (NAT). MethodsWomen with Stage II or III HER2-positive BC who received anthracycline-taxane-trastuzumab NAT regimens followed by curative-intent surgery were included. Patients were classified according to tumor HER2 expression into HER2-high (immunohistochemistry (IHC) 3+ or fluorescence in situ hybridization (FISH) HER2/CEP17 ratio ≥5 or HER2 copy number ≥10) and HER2-intermediate (IHC 2+ with HER2/CEP17 ratio ≥2 to <5 or copy number ≥4 to <10). Univariate and multivariate logistic regression analyses were performed using HER2 expression as a categorical variable. The primary outcome was pathological complete response (pCR). Estimated 3-year disease-free survival (DFS) and Overall Survival (OS) were secondary outcomes. ResultsAmong 161 patients with HER2-positive BC, 139 (86%) and 22 (14%) were classified as HER2-high and HER2-intermediate, respectively; 105 (65.2%) had hormone receptor (HR)-positive tumors; 72 (45%) achieved a pCR. In the overall population, pCR rates of 18% and 49% were achieved in HER2-intermediate and HER2-high cases, respectively (odds ratio [OR] = 0.23 95% CI 0.07-0.72; P = .007). No pCRs were observed among HR-positive, HER2-intermediate cases. Estimated 3-year DFS was 97.1% versus 89.3% for patients achieving a pCR versus those with residual disease, respectively (P = .0011). ConclusionWe found that patients with HER2-high disease were more likely to achieve pCR after NAT compared to patients with HER2-intermediate BC, a subgroup of patients that may benefit from more personalized NAT strategies.

Genotype-Directed Synthetic Cytotoxicity of ATR Inhibition with Radiotherapy.

The importance of the DNA damage response in mediating effects of radiotherapy (RT) has galvanized efforts to target this pathway with radiosensitizers. Yet early clinical trials of this approach have failed to yield a benefit in unselected populations. We hypothesized that ataxia-telangiectasia mutated (Atm)-null tumors would demonstrate genotype-specific synergy between RT and an inhibitor of the DNA damage response protein ataxia-telangiectasia and Rad3-related (ATR) kinase. We investigated the synergistic potential of the ATR inhibitor (ATRi) RP-3500 and RT in two Atm-null and isogenic murine models, both in vitro and in vivo. Staining of γ-H2AX foci, characterization of the immune response via flow cytometry, and tumor rechallenge experiments were performed to elucidate the mechanism of interaction. To examine genotype specificity, we tested the interaction of ATRi and RT in a Brca1-null model. Finally, patients with advanced cancer with ATM alterations were enrolled in a phase I/II clinical trial to validate preclinical findings. Synergy between RP-3500 and RT was confirmed in Atm-null lines in vitro, characterized by an accumulation of DNA double-strand breaks. In vivo, Atm-null tumor models had higher rates of durable control with RT and ATRi than controls. In contrast, there was no synergy in tumors lacking Brca1. Analysis of the immunologic response indicated that efficacy is largely mediated by cell-intrinsic mechanisms. Lastly, early results from our clinical trial showed complete responses in patients. Genotype-directed radiosensitization with ATRi and RT can unleash significant therapeutic benefit and could represent a novel approach to develop more effective combinatorial synthetic cytotoxic RT-based treatments.

Combined Chemotherapy and Immunotherapy Induction for Screening of Patients with Cervical Esophageal Carcinoma for Subsequent Local Treatment: A New Treatment Paradigm

BackgroundDefinitive chemoradiotherapy is recommended as the primary treatment for cervical esophageal carcinoma (CEC). However, local control rates remain unsatisfactory for some patients. Therefore, in this study, we introduced a new treatment paradigm for individuals with CEC, customizing the choice between subsequent local treatments based on their response to induction chemotherapy and immunotherapy.Patients and MethodsInduction treatment comprised two to four cycles of chemotherapy combined with programmed cell death protein 1 (PD-1) inhibitors. Patients achieving complete response (CR) or near CR after induction treatment underwent definitive chemoradiotherapy (dCRT), while those not achieving CR or near CR underwent surgical resection.ResultsAmong the 40 eligible patients, 14 (35.0%) achieved a CR or near CR after induction treatment. Of the ten patients achieving a CR or near CR, one developed an esophageal fistula after dCRT (10.0%). Among the eight non-CR or non-near CR patients receiving chemoradiotherapy, six developed esophageal fistula (75.0%). Among the 26 patients who did not achieve CR or near CR after induction treatment, the 1-year cancer specific survival (CSS) rates were 93.3% [95% confidence interval (CI) 0.815–1%] for the 18 patients in the surgery group, and 71.4% (95% CI 0.447–1%) for the 8 patients in the chemoradiotherapy group (p = 0.027). The overall laryngeal preservation rate was 85.0% (34/40), with a functional laryngeal preservation rate of 77.5% (31/40).ConclusionThe approach consisting of combined immunotherapy and chemotherapy successfully identified patients who were responding well to induction treatment and who were sensitive to radiotherapy, for chemoradiotherapy; thus, improving laryngeal preservation rates. In addition, it also identified patients with poor responses to induction treatment and radiotherapy, for timely surgery; hence, reducing radiotherapy complications and enhancing survival.

PIKfyve controls dendritic cell function and tumor immunity.

The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-κB pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

Pathological Complete Response in Patients With Resected Pancreatic Adenocarcinoma After Preoperative Chemotherapy

Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma, leading to pathological complete response (pCR) in a small subset of patients. However, multicenter studies with in-depth data about pCR are lacking. To investigate the incidence, outcome, and risk factors of pCR after preoperative chemo(radio)therapy. This observational, international, multicenter cohort study assessed all consecutive patients with pathology-proven localized pancreatic adenocarcinoma who underwent resection after 2 or more cycles of chemotherapy (with or without radiotherapy) in 19 centers from 8 countries (January 1, 2010, to December 31, 2018). Data collection was performed from February 1, 2020, to April 30, 2022, and analyses from January 1, 2022, to December 31, 2023. Median follow-up was 19 months. Preoperative chemotherapy (with or without radiotherapy) followed by resection. The incidence of pCR (defined as absence of vital tumor cells in the sampled pancreas specimen after resection), its association with OS from surgery, and factors associated with pCR. Factors associated with overall survival (OS) and pCR were investigated with Cox proportional hazards and logistic regression models, respectively. Overall, 1758 patients (mean [SD] age, 64 [9] years; 879 [50.0%] male) were studied. The rate of pCR was 4.8% (n = 85), and pCR was associated with OS (hazard ratio, 0.46; 95% CI, 0.26-0.83). The 1-, 3-, and 5-year OS rates were 95%, 82%, and 63% in patients with pCR vs 80%, 46%, and 30% in patients without pCR, respectively (P < .001). Factors associated with pCR included preoperative multiagent chemotherapy other than (m)FOLFIRINOX ([modified] leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) (odds ratio [OR], 0.48; 95% CI, 0.26-0.87), preoperative conventional radiotherapy (OR, 2.03; 95% CI, 1.00-4.10), preoperative stereotactic body radiotherapy (OR, 8.91; 95% CI, 4.17-19.05), radiologic response (OR, 13.00; 95% CI, 7.02-24.08), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76; 95% CI, 1.79-7.89). This international, retrospective cohort study found that pCR occurred in 4.8% of patients with resected localized pancreatic adenocarcinoma after preoperative chemo(radio)therapy. Although pCR does not reflect cure, it is associated with improved OS, with a doubled 5-year OS of 63% compared with 30% in patients without pCR. Factors associated with pCR related to preoperative chemo(radio)therapy regimens and anatomical and biological disease response features may have implications for treatment strategies that require validation in prospective studies because they may not universally apply to all patients with pancreatic adenocarcinoma.

A nomogram to predict the pathological complete response in patients with breast cancer based on the TILs-US score.

The tumor-infiltrating lymphocytes-ultrasonography score is a calculation system for predicting lymphocyte-predominant breast cancers in surgical specimens. A nomogram based on the tumor-infiltrating lymphocytes-ultrasonography score was developed to predict the pathological complete response in breast cancer treated with neoadjuvant chemotherapy. A retrospective evaluation was conducted on 118 patients with breast cancer treated with neoadjuvant chemotherapy at Hiroshima University Hospital. Tumor-infiltrating lymphocytes-ultrasonography scores ≥4 were classified as high. A nomogram was developed using a stepwise logistic regression model for pathological complete response (ypT0 ypN0), based on the smallest Akaike information criterion. The predictive ability and clinical usefulness of the nomogram were also evaluated. Among 118 patients, 34 (28.8%) achieved a pathological complete response, and 52 (44.1%) exhibited high tumor-infiltrating lymphocytes-ultrasonography. In multivariate logistic regression analysis, high tumor-infiltrating lymphocytes-ultrasonography (odds ratio, 6.01; P<0.001), clinical complete response (odds ratio, 4.83; P=0.004) and hormone receptor (odds ratio, 3.48; P=0.038) were independent predictors of pathological complete response. A nomogram based on tumor-infiltrating lymphocytes-ultrasonography score, clinical complete response, hormone receptor and clinical N status was developed. The nomogram showed an area under the curve of 0.831 and a bias-corrected area under the curve of 0.809. The calibration plot showed a good fit between the expected and actual pathological complete response values. Decision curve analysis also showed the clinical utility of the nomogram for predicting pathological complete responses. A nomogram based on the tumor-infiltrating lymphocytes-ultrasonography score exhibited a favorable predictive ability for pathological complete response in patients with breast cancer, which can be useful in predicting the residual disease status after neoadjuvant chemotherapy.

Impact of regulatory t cells in peripheral blood on pathological complete response in patients with locally advanced gastric or gastroesophageal junction cancer undergoing neoadjuvant chemoimmunotherapy.

e16081 Background: Neoadjuvant chemotherapy has become the standard treatment for locally advanced gastric or gastroesophageal junction (G/GEJ) cancer. With the widely clinical application of immune checkpoint inhibitors, represented by anti-PD-1 antibodies, an increasing number of patients with locally advanced G/GEJ cancer are undergoing neoadjuvant chemoimmunotherapy. However, there is currently no effective predictive marker for neoadjuvant chemoimmunotherapy in locally advanced G/GEJ cancer. We explored the role of peripheral blood regulatory T (Treg) cells in patients with locally advanced G/GEJ cancer. Methods: We retrospectively analyzed lymphocyte subpopulations before and after treatment in patients with locally advanced G/GEJ cancer who received neoadjuvant chemotherapy combined with anti-PD-1 antibodies and curative surgery. Inclusion criteria were: 1) Pathologically confirmed adenocarcinoma of the G/GEJ; 2) Clinically staged as gastric cT3-4 or N+ without distant metastasis by enhanced CT and endoscopic ultrasound examination; 3) Patients requiring neoadjuvant treatment according to gastric cancer multidisciplinary team decisions; 4) Receipt of neoadjuvant treatment with chemotherapy combined with PD-1 antibodies; 5) Completion of 3-4 cycles of treatment; 6) Underwent curative resection; 7) Lymphocyte subpopulation testing performed before the first and second cycles. Results: From July 1, 2020, to May 31, 2023, 85 patients were included. All 85 patients underwent D2 radical surgery and achieved R0 resection, with 21 patients achieving pathological complete response (pCR), resulting in a pCR rate of 24.7% (95% confidence interval (CI) 15.3-34.1%). There were no statistically significant differences in baseline characteristics between the pCR and non-pCR groups. There were no statistically significant differences in lymphocyte subpopulations between the baseline pCR and non-pCR patient groups. After one cycle of treatment (before the second cycle), there were statistically significant differences in lymphocytes, T lymphocytes, and Treg cells between the two groups. Further analysis of the absolute changes in lymphocyte subpopulations before and after one cycle of treatment revealed a greater decrease in Treg cells in the pCR group. Based on the increase or decrease in Treg cells after one cycle of treatment, the 85 patients were divided into Treg cell increase and decrease groups. The pCR rate was 11.4% (4/35, 95% CI 0.3-22.5%) in the Treg cell increase group and 34% (17/50, 95% CI 20.4-47.6%) in the Treg cell decrease group, with a statistically significant difference between the two groups ( P= 0.022). Conclusions: In locally advanced G/GEJ cancer, changes in Treg cells after one cycle of neoadjuvant treatment may serve as a predictive marker for achieving pCR.

Evaluating gut microbiome as a biomarker of pathological complete response in patients with early locally advanced triple negative breast cancer (LA TNBC): A pilot study.

593 Background: It has previously been shown that microbial metabolic pathways are differentially activated in immunotherapy resistance, hence can serve as potential biomarker as well as target for therapeutic intervention. With the advent of Immune Checkpoint Blockers (ICB) in the neoadjuvant (NA) setting of locally advanced (LA) TNBC, we hypothesized that similar microbial metabolite mediated resistance may be at play. We are presenting data demonstrating differences in microbiome and metabolites in these patients. Methods: 28 patients who received NA pembrolizumab and chemotherapyfor LA TNBC were identified at Moffitt Cancer Center and Tampa General Hospital between February 2022 to October 2023. Blood and stool samples were collected at therapy initiation, at completion of neoadjuvant treatment and/or when the patients developed grade 3 or higher toxicity to therapy. We evaluated stool metagenomics and untargeted stool/plasma metabolomics as correlatives. Patient characteristics were as follows: 21 Caucasian, 3 African-American, 2 Hispanic, 2 unknown, median age 51 years, median body mass index (BMI) 28.5 kg/m2. 17 patients had stage II, while 11 patients had stage III TNBC. Results: Response was assessed in 27 patients, of which 11 had pCR (ypT0/is ypN0) while 16 had residual disease (RD). 1 patient progressed, while on NA therapy, while 8 patients developed grade 3-4 immune related adverse events leading to treatment discontinuation and death in one patient. We conducted shallow shotgun metagenomic sequencing and untargeted metabolomic profiling on pre and post treatment fecal and plasma samples respectively to identify gut microbial diversity, composition and differentially abundant metabolites associated with pCR.There wasno difference in alpha and beta diversity; however significant enrichment of microbiota with genus Akkermansia HR 0.04, p 0.03 was noted in those with pCR. We observed higher abundance of tryptophan metabolizing clostridium species HR 50541, p &lt;0.001, along with differential activation of microbial tryptophan pathway in those with residual disease, specifically higher abundance of hydroxyindole acetic acid HR 1.54 P&lt;0.005, indole propionic acid HR 1.75 p 0.05 and indole butyric acid HR 1.86 p 0.04. Conclusions: To our knowledge this is the first analysis of differences in the microbiome and microbial metabolism in patients with LA TNBC treated with NA ICB. Despite being a small study, it shows a more aggressive disease pattern with higher RD than noted in KEYNOTE 522 and shows significant concern for serious immune mediated adverse effects. This highlights the importance of biomarkers to stratify patients most likely to benefit from ICB. Enrichment of microbiota and immunosuppressive tryptophan metabolites were associated with pCR and should be validated in large studies as biomarker of response to NA ICB in TNBC.

Pathologic complete response in patients with localized soft tissue sarcoma treated with neoadjuvant therapy and its correlation with clinical outcomes: A systematic review.

e23529 Background: Soft tissue sarcomas (STS), comprising approximately 1% of adult solid malignancies, are primarily treated with surgery, with the choice of perioperative treatment being a challenging and highly individualized decision. Clinical trials assessing neoadjuvant modalities in STS predominantly use clinical outcomes or radiologic response as endpoints, with pathologic complete response (pCR) typically not being employed as a designated study endpoint. There is a growing inclination towards neoadjuvant treatment for STS. While pCR serves as a crucial marker guiding treatment decisions in other neoplasms like breast cancer and urothelial cancer, it is not yet used in a similar setting for STS. Our systematic review aimed to assess the rates of pCR in clinical trials of different neoadjuvant modalities for STS and its correlation with patient clinical outcomes. Methods: A systematic literature search was conducted, with eligibility criteria being prospective or retrospective, phase I, II or III trials testing neoadjuvant treatments for STS. Neoadjuvant treatments were chemotherapy, radiotherapy, TKIs or combinations of the above. 23 studies were included, from which data regarding rates of pCR with each treatment, as well as the correlation of pCR with clinical outcomes, were retrieved. Results: Of the 23 trials included, seven did not assess pCR. In the remaining 16 trials, pCR was defined by either ≥90% or ≥95% pathologic necrosis in the tumor specimen. The percentage of patients who achieved pCR ranged from 8 to 58%. Most of these trials did not assess an association between pCR and clinical outcomes. However, among those investigating this correlation, a positive association was identified between pCR and both 5-year disease-specific survival (DSS) and 5-year overall survival (OS). Table 1 summarizes the eight trials that sought to correlate rates of pCR with clinical outcomes. Conclusions: Our findings indicate pCR variability across different neoadjuvant treatments for STS and a possible positive correlation with patient outcomes. Consequently, we propose considering pCR as a surrogate endpoint in future prospective trials for STS that might guide further treatment decisions. [Table: see text]

Treatment-free survival after immunotherapy discontinuation in advanced melanoma: A systematic review and meta-analysis of real-world studies.

e21523 Background: Immune checkpoint inhibitors (ICIs) have altered the treatment landscape of advanced melanoma with remarkable improvements in progression-free survival (PFS). Durable responses to ICI cessation have been shown in early clinical trials for ICI usage in melanoma, although the optimal duration of immunotherapy remains unclear. Treatment-free survival (TFS) after immunotherapy cessation for patients with complete response (CR), partial response (PR), and stable disease (SD) has been reported in real-world studies and may help to guide discontinuation of ICI therapy. Methods: A systematic search was conducted using PubMed, Embase, and the Cochrane Library to identify real-world studies reporting TFS after immunotherapy in advanced cutaneous melanoma patients with CR, PR, and SD at 12 and 24 months. Discontinuation due to iRAEs were included. Effect sizes were pooled using a random-effects model using the meta and metafor packages in R after logit transformation. Inter-study heterogeneity was quantified using I2 statistic. Results: Systematic review yielded 34 studies investigating TFS in prospective and retrospective studies. Of these, three retrospective cohort studies reported real-world TFS at 12 and 24 months. Overall, 738 patients with advanced melanoma were included in this meta-analysis, with 384 patients in CR, 278 patients in PR, and 76 patients in SD at time of ICI discontinuation. Mean patient age was 66.4 and 61.9% of patients were male. Pooled 12 and 24-month TFS proportions were higher for patients with CR than PR and for patients with PR than SD. Pooled 24-month TFS was statistically significantly greater in patients with CR compared to SD. I2 statistics showed considerable heterogeneity between studies ( &gt; 80% in CR and PR subgroups). Conclusions: 12 and 24-month TFS after ICI discontinuation was significant for patients with CR and PR to therapy, suggesting the feasibility of ICI discontinuation in patients after therapy response. Pooled 12-month TFS for patients with SD was 66%, although with decline to 36% at 24 months. Limitations of this meta-analysis include a limited number of included studies. Further research is needed to determine the optimal duration of ICI therapy for patients with advanced melanoma depending on best overall therapy response. [Table: see text]

Phase 1 study of GT101 as an autologous tumor infiltrating lymphocyte (TIL) therapy in advanced solid tumors.

2548 Background: Adoptive cell therapy utilizing autologous TIL has demonstrated efficacy and durable long-term responses in patients with certain advanced solid tumors progressed after conventional therapies. We present data from 14 patients enrolled in the study of GT101, a Phase 1, open-label, single-arm, multicenter trial (NCT05430373) of autologous TIL therapy, aiming to investigate the safety profile, efficiency trend and the duration of response. Methods: The trial was designed with the primary endpoint on evaluating DLT and characterizing the safety profile of GT101 in solid tumor patients measured by the incidence of Grade ≥ 3 treatment-emergent adverse events (TEAEs). The secondary endpoints were to assess efficacy parameters including overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS) according to RECIST v1.1. Results: As of November 10, 2023, a cohort of 14 patients received treatment with a median age of 46.9 and a median of 2.6 lines of prior therapies. Following a standard FC-based lymphodepletion, patients underwent GT101 infusion at doses ≥ 5x109 cells with median dose of 3.7x1010 cells, followed by high-dose IL-2 administration. Most of observed Grade ≥ 3 AEs were related to the FC conditioning regimen and IL-2, including decreased lymphocyte count, decreased white blood cell count, decreased neutrophil count, anemia, pyrexia and decreased platelet count. The majority of these AEs were recovered within 14 days, while a few were downgraded to ≤ Grade 2 within 4 weeks. Among 14 enrolled patients across various indications (small-cell-lung cancer, melanoma, cervical cancer), the ORR was 35.7%. Specifically, 4 pts (28.6%) had a confirmed partial response (PR), 1 pt (7.1 %) achieved complete response (CR), and 8 pts (57.1 %) had stable disease (SD) as their best response. One pt had unconfirmed disease progression (PD). Notably, among 11/14 patients with cervical cancer, the ORR was 45.5% (5/11) with 4 pts (36.4%) achieving PR and 1 pt (9.1 %) achieving CR. Disease control was observed in 10/11 pts (90.9%), and the median PFS was 4.2 months for this cohort. The CR patient underwent a long-term follow-up and the duration of CR and PFS (estimated by Kaplan-Meier) was 24 weeks and 36 weeks, respectively. Post GT101 infusion, T cell expanded robustly in the peripheral blood of all patients with median Tmax 6.83 days and average 15.9 days. Conclusions: In the GT101 Phase 1 study, no treatment-related SAEs and DLT were observed. In patients with heavily pretreated advanced or metastatic solid tumors, GT101 exhibited a manageable safety profile under the treatment protocol of lymphodepletion and high-dose IL-2 and a favorable clinical profile, particularly in cervical cancer, with an encouraging ORR and sustained response duration. Clinical trial information: NCT05430373 .

Abstract PO4-03-07: The impact of chemotherapy relative dose intensity on pathological complete response in patients with triple negative breast cancer treated with neoadjuvant chemotherapy

Abstract Background: Neoadjuvant chemotherapy (NACT) is the preferred treatment approach for early-stage triple negative breast cancer (TNBC). Achieving pathologic complete response (pCR) after NACT is associated with improved event-free survival and overall survival in patients with TNBC. Major research efforts have been deployed to identify predictive biomarkers for pCR in TNBC. However, the values of chemotherapy (CT) relative dose intensity (RDI) in predicting pCR remain unclear. Methods: A retrospective analysis was conducted among 96 consecutive patients with early stage TNBC who received NACT between February 2018 and January 2023 at the University of Naples Federico II (Naples, Italy). Patients’ demographics, clinical-pathological features, and type of CT schedules were retrieved from electronic medical records. pCR was defined as the absence of residual invasive or in situ carcinoma in primary tumor and/or lymph nodes, upon chemotherapy administration. RDI was calculated as the ratio of delivered to planned CT dose intensity. RDI was defined as low if &amp;lt; 85% or high if ≥85%, respectively. Univariate and multivariate logistic regression were used to evaluate the association between age, tumor stage, RDI, CT regimen dose type, and pCR. Results: All patients were included in the analysis. Median age at diagnosis was 51 years (range 28-75). Sixty-five (68%) and 31 (32%) patients were diagnosed with stage II and stage III TNBC, respectively. Nineteen (19%) patients received a sequential schedule of anthracycline plus cyclophosphamide (AC) and a taxane (T). Sixty-one (64%) patients received AC followed by concurrent carboplatin-paclitaxel (CaP). Sixteen (17%) patients received the anti-PD1 pembrolizumab in addition to ACCaP chemotherapy backbone (ACCaP-Pem). Fifty-four (56%) patients received a dose-dense AC-based CT. A pCR was achieved in 59 (61%) patients. Interestingly, patients who received a dose-dense AC based neoadjuvant CT had higher chance to achieve a pCR compared with those treated with a non dose-dense AC based CT (70% vs 46%, p = 0.03). Overall, 79 (82%) and 17 (18%) patients received a RDI high and RDI low CT, respectively. No difference in terms of age, body mass index, performance status, tumor stage, type of chemotherapy was observed between the two groups (Table 1). At univariate analysis RDI high (OR 5.18, 95%CI: 1.65-16.31, p=0.005) and dose dense AC-based CT (OR 2.42, 95%CI: 0.18-0.97, p=0.04) were significantly associated with pCR. In a multivariate model including RDI, age, tumor stage, and AC regimen dose type, RDI was the only variable independently associated with pCR (OR 4.60, 95% CI: 1.40-15.06, p = 0.01). Conclusion: A chemotherapy RDI≥ 85% independently predicts pCR in early stage TNBC patients treated with standard NACT. In our cohort, one in five patients received a suboptimal chemotherapy dose intensity affecting at least in part tumor response. Studies with larger TNBC patient populations are warranted to confirm the impact of RDI on pCR and long-term outcomes. Table 1 Citation Format: Roberto Buonaiuto, Giuseppe Neola, Aldo Caltavituro, Paola Trasacco, Federica Pia Mangiacotti, Giovanna Pecoraro, Matteo Lambertini, Erica Pietroluongo, Pietro De Placido, Sabino De Placido, Valeria Forestieri, Mario Giuliano, Grazia Arpino, Carmine De Angelis. The impact of chemotherapy relative dose intensity on pathological complete response in patients with triple negative breast cancer treated with neoadjuvant chemotherapy [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 PO4-03-07.

A Retrospective Review and Comprehensive Tumour Profiling of Advanced Non-Melanomatous Cutaneous Spindle Cell Neoplasms Treated with Immune-Checkpoint Inhibitors.

Non-melanomatous cutaneous spindle cell neoplasms are a rare group of malignancies that present a diagnostic challenge, and for which there is a lack of consensus on how to best manage patients with advanced disease and only limited reports of immune-checkpoint inhibitor (ICI) responses. In this study, we performed a single-center retrospective review of treatment outcomes for all advanced non-melanomatous cutaneous spindle cell neoplasms treated with ICIs. Blinded histopathology reviews occurred to confirm each diagnosis. Comprehensive tumour profiling included whole exome sequencing for tumour mutational burden (TMB) and ultraviolet(UV) signatures, and immunohistochemistry for immune-cell infiltration (CD4/CD3/CD8/CD103/CD20) and immune-checkpoint expression (PD-L1/LAG3/TIGIT). Seven patients were identified. The objective response rate was 86% (6/7) with five complete responses (CR). Responses were durable with two patients in CR > 30 months after ICI commencement. All patients had high TMB and UV signatures. One patient had PD-L1 100% (combined positive score) with abundant immune-cell infiltration and LAG3 expression. In advanced non-melanomatous cutaneous spindle cell neoplasms, excellent responses to ICIs with durable disease control were observed. ICIs are worthy of further exploration in these patients. UV signatures and high TMB could be used to help select patients for treatment.

Quality of life after immune suppressive therapy in aplastic anemia.

Acquired aplastic anemia (AA) is a rare form of immune-mediated bone marrow failure, which can result in life-threatening infections or bleeding if left untreated. Treatment consists of either immune suppressive therapy (IST) or allogeneic stem cell transplantation (alloHSCT). While considerable research has been published regarding survival, response rate and toxicity of both treatments, knowledge on the impact on quality of life (QoL) is scarce. We used the recently developed AA-specific QoL questionnaire (QLQ-AA/PNH-54) to evaluate QoL in a single center cohort of AA patients who were successfully treated with IST. The 54 questions represent 12 different QoL domains. Results were analyzed for all patients and grouped based on hematologic response (complete response (CR) or partial response (PR)). Thirty-six successfully treated adult patients (15 in CR, 21 in PR) completed the questionnaire (median age 54years, range 21-71; median time since last IST 5years, range 0-41). Fatigue was experienced by 83% of patients. Even though total QoL scores did not significantly differ between patients with PR and CR (105 vs 92, p-value 0,17) there appeared to be a trend towards higher scores in patients with PR, especially in domains concerning psychological wellbeing. This trend was most clear in the domains fear of progression (2,12 in PR patients vs 1,73 in CR patients; p-value 0,08) and role functioning (2,22 vs 1,88; p-value 0,07). In conclusion, patients with AA continue to experience psychological and physical effects despite successful IST.

Abstract 6203: An altered profile of ribosomal proteins and ERK-eIF4E translational control in an inflammatory breast cancer model of acquired resistance and reversal is associated with pathological complete response in patients

Abstract Background: Drug resistance is a major challenge in inflammatory breast cancer (IBC), a hyperproliferative subtype characterized by the presence of diffuse tumor cell clusters that show high level of heterogeneity. As the degree of tumor heterogeneity during cancer progression can cause evolution of cell states that can either compete or co-operate resulting in therapeutic failure, the study objective was to identify drug resistance networks that can serve as biomarkers or therapeutic targets. Methods: Integrated transcriptomic and proteomic profiling approach was conducted in a progression model of acquired drug resistance and its reversal comprised of a treatment-naïve patient-derived SUM149 cell line, along with two isogenic derivatives and representing drug-resistant (rSUM149) and resistance-reversal states (rrSUM149). Global gene expression analysis in IBC patients (n=87) recorded responses to neoadjuvant chemotherapy. Based on the data, targeted multikinase inhibitors were evaluated in viability and signaling assays. Results: We identified specific ribosomal proteins associated with resistance acquisition, which correlated with high levels of pERK, CDK1, XIAP, and SOD2. Conversely, the resistance reversal in rrSUM149 showed almost complete normalization to the profile of SUM149. However, VIPER analysis revealed proteins related to ribosomal processes (AGO2, Exportin 1, RPL5) that did not revert in rrSUM149, suggesting this pathway may have pleiotropic effects in governing drug resistance. Notably, genes linked to ribosomal processes were significantly enriched (P&amp;lt;0.001) among the overexpressed genes in IBC patients (n=87) who exhibited pCR to neoadjuvant chemotherapy. This is crucial as IBC tumors, including rSUM149, exhibit MAPK hyperactivation including in the presence of EGFR tyrosine kinase inhibitors. Treatment with Merestinib, a multikinase inhibitor, suppressed pERK, peIF4E, downstream targets like CDK1, and ribosomal protein IMP3 underscoring the impact on protein synthesis signaling crucial for countering translational dependence in cancer cells. Additionally, Merestinib synergized with EGFR-TKI (lapatinib) in increasing cell death in all three states. Conclusion: Overall, our study describes adaptive changes in response to both therapeutic stress and therapy break that have the potential to serve as biomarkers or extended for pharmacological interrogation toward precision medicine for this rare, understudied cancer. Furthermore, the ability of Merestinib, in clinical trials, to target translational dependence is attractive as cancer cells often appropriate these signaling pathways to gain tolerance to various stress stimuli. Support: NIH-R01CA264529; DoD Breast Cancer Breakthrough level 2 Award W81XWH2010153 Citation Format: Gayathri R. Devi, Pritha PAI, Matthew W. Foster, Dorababu S. Sannareddy, Seayoung Lee, Steven V. Laere. An altered profile of ribosomal proteins and ERK-eIF4E translational control in an inflammatory breast cancer model of acquired resistance and reversal is associated with pathological complete response in patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6203.

Abstract 5094: Immunotherapy in advanced cutaneous non-melanomatous spindle cell neoplasms

Abstract Background: Non-melanomatous cutaneous spindle cell neoplasms (NMCSpC) are a rare group of malignancies including pleomorphic dermal sarcoma (PDS) and spindle-cell cutaneous squamous cell carcinoma (SpSCC). They present a diagnostic challenge with overlapping morphological features and variable patterns of immunohistochemical (IHC) staining. There is a lack of consensus on how to best manage advanced NMCSpC and limited reports of immunotherapy (IO) responses. This study reviews the efficacy of IO in NMCSpC and performs comprehensive tumor profiling to identify biological rationale for IO use in this rare group of tumors. Methods: We performed a single-center retrospective review of all locally-advanced or metastatic NMCSpCs treated with IO. Blinded histopathology reviews occurred to confirm each diagnosis. Overall response rates (ORR) were collected as per Response Evaluation Criteria in Solid Tumors 1.1 or Positron Emission Tomography Response Criteria 1.0. Comprehensive tumor profiling included whole exome sequencing for tumor mutational burden (TMB) and ultraviolet(UV)-signatures, and IHC for immune-cell infiltration (CD103/CD4/CD3/CD8/CD20) and immune-checkpoint expression (PD-L1/TIGIT/LAG3). Results: 7 patients were identified. Median follow up was 18.1 months (range: 5.3-34.7). ORR 86% (6/7) with five complete responses (CR). One patient who achieved stable disease progressed. Responses were durable with two patients in CR &amp;gt;30 months after IO commencement. Blinded pathological review identified 3 SpSCC, 2 PDS and 2 spindle cell tumors of unclear sub-classification. All patients had high TMB and UV-signatures. One patient had PD-L1 100% (combined positive score) with abundant immune-cell infiltration and LAG3 expression (Table 1). Conclusion: In advanced NMCSpC, excellent responses to IO with durable disease control was observed. IO is worthy of further exploration in these patients. UV-signatures and high TMB could be used to help select patients for treatment. Immunohistochemistry (IHC)^, tumor mutational burden and ultraviolet signatures Patient T-cell markers B-cell marker Immune-checkpoints Tumor mutational burden (mutations/megabase) Ultraviolet-mutational signature Best response assessment# CD103 CD4 CD3 CD8 CD20 PD-L1 TIGIT LAG3 1 1 20 1 1 0 7 0 0 17.94 Yes Stable metabolic response 2 1 20 30 10 0 100 0 10 35.34 Yes Complete metabolic response 3 1 10 10 5 0 5 0 0 104.87 Yes Complete metabolic response 4 1 0 1 0 0 0 0 0 74.04 Yes Partial metabolic response 5* NA NA NA NA NA NA NA NA 29 Yes Complete metabolic response 6 1 0 0 5 0 0 0 4 12.02 Yes Complete metabolic response 7 1 0 5 1 0 0 0 0 41.17 Yes Complete response ^IHC scores are % of positively stained cells, except for PD-L1 which is combined positive score (CPS). *Insufficient tissue for IHC on Patient 5. #As per PERCIST 1.0 on FDG-PET/CT or RECIST1.1 on CT. Citation Format: Luke S. McLean, Annette M. Lim, Christopher Angel, Richard J. Young, Angela Pizzolla, Stuart Archer, Alesha A. Thai, Benjamin Solomon, Jeremy Lewin, Danny Rischin. Immunotherapy in advanced cutaneous non-melanomatous spindle cell neoplasms [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 5094.