Early Clinical Response Research Articles

Sensitive B-cell receptor repertoire analysis shows repopulation correlates with clinical response to rituximab in rheumatoid arthritis

BackgroundAlthough B-cell depleting therapy in rheumatoid arthritis (RA) is clearly effective, response is variable and does not correlate with B cell depletion itself.MethodsThe B-cell receptor (BCR) repertoire was prospectively analyzed in peripheral blood samples of twenty-eight RA patients undergoing rituximab therapy. Timepoints of achieved BCR-depletion and -repopulation were defined based on the percentage of unmutated BCRs in the repertoire. The predictive value of early BCR-depletion (within one-month post-treatment) and early BCR-repopulation (within 6 months post-treatment) on clinical response was assessed.ResultsWe observed changes in the peripheral blood BCR repertoire after rituximab treatment, i.e., increased clonal expansion, decreased clonal diversification and increased mutation load which persisted up to 12 months after treatment, but started to revert at month 6. Early BCR depletion was not associated with early clinical response but late depleters did show early response. Patients with early repopulation with unmutated BCRs showed a significant decrease in disease activity in the interval 6 to 12 months. Development of anti-drug antibodies non-significantly correlated with more BCR repopulation.ConclusionOur findings indicate that rather than BCR-depletion it is repopulation with unmutated BCRs, possibly from naïve B cells, which induces remission. This suggests that (pre-existing) differences in B-cell turnover between patients explain the interindividual differences in early clinical effect.

Early Immune Remodeling Steers Clinical Response to First-Line Chemoimmunotherapy in Advanced Gastric Cancer.

The benefit of 5-FU/platinum with anti-PD-1 in first-line advanced gastric cancer is limited to patient subgroups. Using a trial with sequential anti-PD-1, we show coordinated induction of multicellular TME hubs informs the ability of anti-PD-1 to potentiate T cell-driven responses. Differential TME hub development highlights features that underlie clinical outcomes. This article is featured in Selected Articles from This Issue, p. 695.

Clarithromycin for early anti-inflammatory responses in community-acquired pneumonia in Greece (ACCESS): a randomised, double-blind, placebo-controlled trial

Addition of macrolide antibiotics to β-lactam antibiotics for the treatment of patients in hospital with community-acquired pneumonia is based on results from observational studies and meta-analyses rather than randomised clinical trials. We investigated if addition of the macrolide clarithromycin to treatment with a β-lactam antibiotic in this population could improve early clinical response-the new regulatory endpoint for community-acquired pneumonia-and explored the possible contribution of modulation of the inflammatory host response to that outcome. The ACCESS trial was a phase 3 prospective, double-blind, randomised controlled trial, in which adults in hospital with community-acquired pneumonia who had systemic inflammatory response syndrome, Sequential Organ Failure Assessment (SOFA) score of 2 or more, and procalcitonin 0·25 ng/mL or more were enrolled in 18 internal medicine departments of public Greek hospitals. Patients were randomly assigned (1:1) by computer-generated block randomisation to standard of care medication (including intravenous administration of a third-generation cephalosporin or intravenous administration of β-lactam plus β-lactamase inhibitor combination) plus either oral placebo or oral clarithromycin 500 mg twice daily for 7 days. Investigators, staff, and patients were masked to group allocation. The primary composite endpoint required that patients fulfilled both of the following conditions after 72 hours (ie, day 4 of treatment): (1) decrease in respiratory symptom severity score of 50% or more as an indicator of early clinical response and (2) decrease in SOFA score of at least 30% or favourable procalcitonin kinetics (defined as ≥80% decrease from baseline or procalcitonin <0·25 ng/mL), or both, as an indicator of early inflammatory response. Participants who were randomly assigned and received allocated treatment were included in the primary analysis population. This trial is complete and is registered with the EU Clinical Trials Register (2020-004452-15) and ClinicalTrials.gov (NCT04724044). Patients were enrolled between Jan 25, 2021, and April 11, 2023, and 278 individuals were randomly allocated to receive standard of care in combination with either clarithromycin (n=139) or placebo (n=139). 134 patients in the clarithromycin group (five withdrew consent) and 133 patients in the placebo group (six withdrew consent) were included in the analysis of the primary endpoint. The primary endpoint was met in 91 (68%) patients in the clarithromycin group and 51 (38%) patients in the placebo group (difference 29·6% [95% CI 17·7-40·3]; odds ratio [OR] 3·40 [95% CI 2·06-5·63]; p<0·0001). Serious treatment-emergent adverse events (TEAEs) occurred in 58 (43%) patients in the clarithromycin group and 70 (53%) patients in the placebo group (difference 9·4% [95% CI -2·6 to 20·9]; OR 0·67 [95% CI 0·42 to 1·11]; p=0·14). None of the serious TEAEs was judged to be related to treatment assignment. Addition of clarithromycin to standard of care enhances early clinical response and attenuates the inflammatory burden of community-acquired pneumonia. The mechanism of benefit is associated with changes in the immune response. These findings suggest the importance of adding clarithromycin to β-lactams for treatment of patients in hospital with community-acquired pneumonia to achieve early clinical response and early decrease of the inflammatory burden. Hellenic Institute for the Study of Sepsis and Abbott Products Operations.

Effectiveness of empiric carbapenem versus non-carbapenem therapy for extended-spectrum β-lactamase producing Enterobacterales infections in non-intensive care unit patients: a real-world investigation in a hospital with high-prevalence of extended-spectrum β-lactamase producing Enterobacterales.

To investigate whether empiric carbapenem therapy, compared to empiric non-carbapenem therapy, was associated with improved clinical outcomes among hospitalized, non-intensive care unit (ICU) patients with extended-spectrum β-lactamase (ESBL)-producing Enterobacterales infections. We performed a retrospective cohort study of adult, non-ICU patients admitted with ESBL-producing Enterobacterales infections. Primary outcome was time to clinical stability from the first empiric antibiotic dose. Secondary outcomes were early clinical response and 30-day all-cause hospital readmission. We used multivariate regression methods to examine time to clinical stability. Of the 142 patients, 59 (42%) received empiric carbapenems and 83 (58%) received empiric non-carbapenems, most commonly ceftriaxone (49/83, 59%). Median age was 59 years. The most common infection source was urinary (71%). The carbapenem group had a higher proportion of patients who received antibiotics within 6 months of admission (55% vs 28%, P < .01) and history of ESBL (57% vs 17%, P < .01). There were no significant differences in hours until clinical stability between the carbapenem and non-carbapenem groups (22 (IQR: 0, 85) vs 19 (IQR: 0, 69), P = .54). Early clinical response (88% vs 90%, P = .79) and 30-day all-cause hospital readmission (17% vs 8%, P = .13) were similar between groups. Among hospitalized non-ICU patients with ESBL-producing Enterobacterales infection, we found no difference in time to clinical stability after the first empiric antibiotic dose between those receiving carbapenems and those who did not. Our data suggest that empiric carbapenem use may not be an important driver of clinical response in patients with less severe ESBL-producing Enterobacterales infection.

212. Effectiveness of Empirical Piperacillin/tazobactam Compared to Cefepime for Bloodstream Infection Caused by Gram-Negative Bacilli

Abstract Background Piperacillin/tazobactam (PTZ) and cefepime (CFP) are commonly used antibiotics for healthcare-associated infections and immunocompromised patients. However, few studies have compared the clinical effectiveness of these two antibiotics. Thus, we compared the effectiveness of empirical PTZ and CFP in patients with monomicrobial blood-stream infection (BSI) caused by gram-negative bacilli. Methods We conducted a retrospective cohort study of consecutive, non-duplicate monomicrobial BSIs caused by 1 of 4 taxa (Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa and Acinetobacter species) identified from a nationwide, prospective surveillance (Korean Antimicrobial Resistance Surveillance Network [KARS-Net]). Patients who were treated with PTZ or CFP as the only active empirical antibiotic were included. The primary outcome was all-cause, in-hospital 30-day mortality. Logistic regression with backward selection was used to adjust for imbalance in baseline characteristics. Results A total of 120 cases were included, among which 87 (72.5%) were treated with PTZ and 33 (27.5%) with CFP. Underlying renal disease was more common in the PTZ group whereas malignancy, septic shock, and neutropenia were more common in the CFP group. (Table 1). All-cause 30-day in-hospital mortality was comparable between the two groups (16.1% vs 12.1%, p=0.777; table 2), as well as attributable mortality. However, the early clinical response at 72 hr was significantly more common in the patients treated with CFP (25.3% vs 57.6%, p=0.001) The choice of empirical antibiotics was not significantly associated with mortality in a multivariable logistic regression model (Table 3). Older age (≥65 years; adjusted OR. 16.24; 95% CI, 2.21-119.60), lower ECOG (aOR, 2.91 per 1 point, 95% CI, 1.35-6.25), high PITT score (aOR, 1.68; 95% CI, 1.17-6.25) and chronic liver disease (aOR, 39.70; 95% CI, 2.56-615.13) were significant independent risk factors for 30-day in-hospital mortality. Conclusion In patients with BSI caused by gram-negative bacilli, empirical use of either PTZ or CFP was associated with comparable clinical outcomes. Disclosures All Authors: No reported disclosures

Early Intestinal Ultrasound Predicts Clinical and Endoscopic Treatment Response and Demonstrates Drug-Specific Kinetics in Moderate-to-Severe Ulcerative Colitis.

Intestinal ultrasound (IUS) is an emerging modality in monitoring disease activity in ulcerative colitis (UC). Here, we aimed to identify early IUS predictors of treatment response as evaluated by endoscopy and assessed the kinetics of IUS changes. This prospective, longitudinal study included UC patients with endoscopic disease activity (endoscopic Mayo score [EMS] ≥2) starting anti-inflammatory treatment. Clinical scores, biochemical parameters and IUS were assessed at baseline (W0), at week 2 (W2), at W6(W6), and at the time of second endoscopy (W8-W26). Per colonic segment, endoscopic remission (EMS = 0), improvement (EMS ≤1), response (decrease in EMS ≥1), and clinical remission (Lichtiger score ≤3) were assessed and correlated with common IUS parameters. Additionally, drug-specific responsiveness of bowel wall thickness (BWT) was assessed. A total of 51 patients were included and followed, and 33 patients underwent second endoscopy. BWT was lower from W6 onward for patients reaching endoscopic improvement (3.0 ± 1.2 mm vs 4.1 ± 1.3 mm; P = .026), remission (2.5 ± 1.2 mm vs 4.1 ± 1.1 mm; P = .002), and clinical remission (3.01 ± 1.34 mm vs 3.85 ± 1.20 mm; P = .035). Decrease in BWT was more pronounced in endoscopic responders (-40 ± 25% vs -4 ± 28%; P = .001) at W8 to W26. At W6, BWT ≤3.0 mm (odds ratio [OR], 25.13; 95% confidence interval, 2.01-3.14; P = .012) and color Doppler signal (OR, 0.35; 95% confidence interval, 0.14-0.88; P = .026) predicted endoscopic remission and improvement, respectively. Submucosal layer thickness at W6 predicted endoscopic remission (OR, 0.09; P = .018) and improvement (OR, 0.14; P = .02). Furthermore, BWT decreased significantly at W2 for infliximab and tofacitinib and at W6 for vedolizumab. BWT and color Doppler signal predicted endoscopic targets already after 6 weeks of treatment and response was drug specific. IUS allows close monitoring of treatment in UC and is a surrogate marker of endoscopy.

DDEL-02. CLINICAL BENEFIT OF BEVACIZUMAB AND IRINOTECAN (BEV+IRI) IN PATIENTS WITH RELAPSED/REFRACTORY GLIOBLASTOMA (R/RGBM) AND ITS POTENTIAL PREDICTORS

Abstract BACKGROUND/AIM: Bevacizumab-containing chemotherapy constitutes an important salvage treatment for recurrent/refractory glioblastoma(r/rGBM). Patients and methods: We retrospectively collected the data of r/rGBM patients treated with the combination of bevacizumab and irinotecan (BEV+IRI) as their salvage treatment from July 2013 and December 2021 in Konkuk Medical Center of Korea. Patients with available results from molecular diagnostic tests were eligible, and markers of interest were examined including the presence of MGMT methylation, IDH1/2 mutation, or 1p/19q co-deletion. Efficacy of BEV+IRI and its potential biomarker was explored. RESULTS: Among 21 patients, 38.1% demonstrated European Cooperative Oncology Group-Performance scale (ECOG-PS) ≥3. The majority (71.4%) received BEV+IRI as their second-line chemotherapies, and the median dose was 5 (range=1-25). Objective response rate (ORR) was 33.3% and disease-control rate (DCR) was 85.7%. Irrespective of objective response, early clinical response was achieved in 14(66.7%) patients. During the median follow-up of 16.4 months for survivors, median progression-free survival (PFS) and overall survival (OS) were 3.6 and 6.8 months, respectively. ECOG PS≥3 and TP53 loss were independent predictors of an unfavorable OS, while prompt clinical improvement could predict favorable OS. Any molecular aberration was associated with OS or PFS in the study. CONCLUSION: Salvage BEV+IRI treatment in r/rGBM conferred comparable clinical benefit. ECOG PS ≥3, TP53 loss, and lack of prompt clinical improvement after the treatment were significantly associated with an unfavorable OS.

H1Innovative approaches to combat anti-cancer drug resistance: Targeting lncRNA and autophagy.

To date, standardizing clinical predictive biomarkers for assessing the response to immunotherapy remains challenging due to variations in personal genetic signatures, tumour microenvironment complexities and epigenetic onco-mechanisms. Early monitoring of key non-coding RNA (ncRNA) biomarkers may help in predicting the clinical efficacy of cancer immunotherapy and come up with standard predictive ncRNA biomarkers. For instance, reduced miR-125b-5p level in the plasma of non-small cell lung cancer patients treated with anti-PD-1 predicts a positive outcome. The level of miR-153 in the plasma of colorectal cancer patients treated with chimeric antigen receptor T lymphocyte (CAR-T) cell therapy may indicate the activation of T-cell killing activity. miR-148a-3p and miR-375 levels may forecast favourable responses to CAR-T-cell therapy in B-cell acute lymphoblastic leukaemia. In cancer patients treated with the GPC3 peptide vaccine, serum levels of miR-1228-5p, miR-193a-5p and miR-375-3p were reported as predictive biomarkers of good response and improved overall survival. Therefore, there is a critical need for further studies to elaborate on the key ncRNA biomarkers that have the potential to predict early clinical responses to immunotherapy. This review summarises important predictive ncRNA biomarkers that were reported in cancer patients treated with different immunotherapeutic modalities including monoclonal antibodies, small molecule inhibitors, cancer vaccines and CAR-T cells. In addition, a concise discussion on forthcoming perspectives is provided, outlining technical approaches for the optimal utilisation of immune-modulatory ncRNA biomarkers as predictive tools and therapeutic targets.

Evaluating [18F]FDG and [18F]FLT Radiotracers as Biomarkers of Response for Combined Therapy Outcome in Triple-Negative and Estrogen-Receptor-Positive Breast Cancer Models.

Breast cancer (BC) is the most frequent cancer and the second leading cause of death in women. A typical feature of BC cells is the metabolic shift toward increased glycolysis, which has become an interesting therapeutic target for metabolic drugs such as metformin (MET). Recently, the administration of the antihypertensive syrosingopine (SYRO) in combination with MET has shown a synergistic effect toward a variety of cancers. However, a fundamental need remains, which is the development of in vivo biomarkers that are able to detect early clinical response. In this study, we exploited a triple-negative murine BC cell line (4T1) and a metastatic ER+ murine BC cell line (TS/A) in order to investigate, in vivo, the early response to treatment, based on MET and/or SYRO administration, evaluating [18F]FDG and [18F]FLT as potential biomarkers via PET/CT. The study provides evidence that SYRO plus MET has a synergistic effect on tumor growth inhibition in both 4T1 and TS/A experimental models and has showed the highest efficacy on the TNBC xenograft mice (4T1) via the expression reduction in the lactate transporter MCT4 and in the epithelial-mesenchymal transition biomarker Snail, promoting its potential application in therapy settings. In addition, the selective reduction in the [18F]FLT tumor uptake (at 7 dd), observed in the SYRO plus MET treated mice in comparison with the vehicle group, suggests that this radiotracer could be potentially used as a biomarker for the early detection of therapy response, in both evaluated xenografts models.

Non-coding RNAs in cancer immunotherapy: Predictive biomarkers and targets.

To date, standardising clinical predictive biomarkers for assessing the response to immunotherapy remains challenging due to variations in personal genetic signatures, tumour microenvironment complexities and epigenetic onco-mechanisms. Early monitoring of key non-coding RNA (ncRNA) biomarkers may help in predicting the clinical efficacy of cancer immunotherapy and come up with standard predictive ncRNA biomarkers. For instance, reduced miR-125b-5p level in the plasma of non-small cell lung cancer patients treated with anti-PD-1 predicts a positive outcome. The level of miR-153 in the plasma of colorectal cancer patients treated with chimeric antigen receptor T lymphocyte (CAR-T) cell therapy may indicate the activation of T-cell killing activity. miR-148a-3p and miR-375 levels may forecast favourable responses to CAR-T-cell therapy in B-cell acute lymphoblastic leukaemia. In cancer patients treated with the GPC3 peptide vaccine, serum levels of miR-1228-5p, miR-193a-5p and miR-375-3p were reported as predictive biomarkers of good response and improved overall survival. Therefore, there is a critical need for further studies to elaborate on the key ncRNA biomarkers that have the potential to predict early clinical responses to immunotherapy. This review summarises important predictive ncRNA biomarkers that were reported in cancer patients treated with different immunotherapeutic modalities, including monoclonal antibodies, small molecule inhibitors, cancer vaccines and CAR-T cells. In addition, a concise discussion on forthcoming perspectives is provided, outlining technical approaches for the optimal utilisation of immunomodulatory ncRNA biomarkers as predictive tools and therapeutic targets.

Omadacycline in the treatment of community-acquired bacterial pneumonia in patients with comorbidities: a post-hoc analysis of the phase 3 OPTIC trial.

The 2019 American Thoracic Society/Infectious Disease Society of America guidelines recommend respiratory fluoroquinolones to treat community-acquired bacterial pneumonia (CABP) in adults with comorbidities. Fluoroquinolones are effective against both typical and atypical pathogens. However, fluoroquinolone treatment has a risk of adverse effects, and the Food and Drug Administration has issued black box safety warnings for their use. Inpatient use of fluoroquinolones has reduced as a result; however, most antibiotic courses are completed as outpatients and discharge prescriptions account for the majority of fluoroquinolone use. As such, a new treatment option is needed to replace fluoroquinolones. Omadacycline is an aminomethylcycline antibiotic with a broad spectrum of activity and is available as a once-daily intravenous or bioequivalent oral formulation. This study assessed the safety and clinical efficacy of omadacycline compared with moxifloxacin for the treatment of adult CABP patients with Pneumonia Severity Index (PSI) risk class II/III and ≥1 comorbidity through a post-hoc analysis of the phase 3 OPTIC study (NCT02531438). In total, 239 omadacycline- and 222 moxifloxacin-treated patients were assessed. The median age was similar between groups (omadacycline: 57 years; moxifloxacin: 58 years), with 26.0% and 26.6%, respectively, ≥65 years of age. Early clinical response was 91.6% for patients with ≥1 comorbidity treated with omadacycline and 91.4% for those treated with moxifloxacin. Post-treatment evaluation results for overall response were 89.1% in the omadacycline group and 87.4% in the moxifloxacin group. Safety warnings have reduced inpatient use of fluoroquinolones; however, outpatient and discharge prescriptions account for the majority of fluoroquinolone use. Outpatients with comorbidities need an efficacious alternative to fluoroquinolones. Omadacycline maintains the similar efficacy and benefits of fluoroquinolones as a once-daily, monotherapy, bioequivalent oral option with potent in vitro activity against the most common CABP pathogens, including S. pneumoniae and atypical pathogens, but offers a materially different safety profile consistent with its tetracycline heritage. In conclusion, both omadacycline and moxifloxacin exhibited similar efficacy in patients with PSI risk class II/III and comorbidities. Omadacycline fulfills an unmet need as an oral monotherapy treatment option for adult patients with CABP, which will further reduce the use of fluoroquinolones. https://www.clinicaltrials.gov/study/NCT02531438, identifer: NCT02531438; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-004071-13, identifier: EudraCT #2013-004071-13.

P94 Bimekizumab early treatment response translated into cumulative benefits in health-related quality of life in patients with moderate-to-severe plaque psoriasis: results from 2 years of the BE RADIANT phase IIIb trial

Abstract Speed of response is a key treatment goal for patients with psoriasis. This analysis aimed to assess how early clinical response translated into cumulative health-related quality of life (HRQoL) benefit in patients with moderate-to-severe plaque psoriasis over 2 years of bimekizumab (BKZ) treatment. Included patients from BE RADIANT were randomized to BKZ 320 mg every 4 weeks (Q4W), continued to receive Q4W dosing or switched to Q8W at week 16 and entered the open-label extension (OLE) at week 48 (receiving BKZ Q4W or Q8W; NCT03536884). The proportions of patients achieving Psoriasis Symptoms and Impacts Measure (P-SIM) 0 in itching, skin pain and scaling, and Dermatology Life Quality Index 0 or 1 (DLQI 0/1), were estimated using modified nonresponder imputation (mNRI); missing data were imputed via NRI for patients discontinuing due to the lack of efficacy or treatment-related adverse events and multiple imputation otherwise. Cumulative HRQoL and symptom benefit through to week 96 was estimated using the area under the curve (AUC0–96) by week 16 Psoriasis Area and Severity Index (PASI)-100 status (NRI), with week 16 and week 96 responses also reported. AUC0–96 was used to calculate the estimated number of days that each response was achieved. Of the 336 patients randomized to BKZ who entered the OLE, 216 achieved PASI 100 at week 16. Of these, 187/216 patients had already achieved PASI 100 at one or more visit(s) before week 16. Of the PASI-100 responders at week 16, 71.8%, 92.1%, 89.4% and 88.0% also achieved P-SIM 0 for itching, skin pain and scaling and DLQI 0/1, respectively, vs. 39.1%, 77.7%, 56.6% and 74.6% of nonresponders. Of the week 16 PASI-100 responders at week 96, 67.1%, 85.4%, 80.6% and 89.3% achieved P-SIM 0 for itching, skin pain and scaling and DLQI 0/1, respectively, vs. 55.6%, 77.7%, 63.7% and 80.8% of nonresponders. The total AUC0–96 for achievement of P-SIM 0 in itching, skin pain and scaling and DLQI 0/1 was greater for week 16 PASI-100 responders through 2 years, corresponding to a greater number of days achieving these outcomes vs. nonresponders (Table 1). A high proportion of patients achieved complete skin clearance at week 16, translating to a greater number of days achieving P-SIM 0 in itching, skin pain and scaling and DLQI 0/1 vs. week 16 PASI-100 nonresponders through 2 years of BKZ treatment.Table 1AUC0-96 by week 16 PASI-100 response over 2 years (mNRI)Week 16 PASI-100 responders (n = 216)Week 16 PASI-100 nonresponders (n = 120)P-SIM 0P-SIM 0ItchingSkin painScalingDLQI 0/1ItchingSkin painScalingDLQI 0/1AUC0–9666398504784982674918753957837584Days465595549579344528405531 Acknowledgment: Medical writing: Costello Medical. Funding sources: UCB Pharma.

High-Frequency Electroporation and Chemotherapy for the Treatment of Cutaneous Malignancies: Evaluation of Early Clinical Response.

High-frequency electroporation (HF-EP) with chemotherapy is a novel therapy proposed for both curative and palliative treatment of cutaneous malignancies. The use of high-frequency biphasic pulses is thought to reduce the painful muscle contractions associated with traditional electrochemotherapy (ECT), allowing treatment administration under local anaesthesia. This proof-of-concept study investigated the efficacy and tolerability of HF-EP protocols on a variety of cutaneous malignancies. A total of 97 lesions of five different histological subtypes were treated across 25 patients. At 12 weeks post-treatment, a 91.3% overall lesion response rate was observed (complete response: 79%; partial response: 12.3%), with excellent intraprocedural patient tolerability under local anaesthetic. HF-EP with chemotherapy shows promising results regarding tumour response rates for cutaneous malignancies of varying histological subtypes when compared to traditional ECT protocols. Improved patient tolerability is important, increasing the possibility of treatment delivery under local anaesthesia and potentially broadening the treatment envelope for patients with cutaneous malignancies.

The amount of surgery in patients with early breast cancer and complete clinical response to neoadjuvant systemic therapy

BACKGROUND: Neoadjuvant systemic therapy for triple-negative and HER2-positive breast cancer can achieve a complete pathologic response in approximately 60% of patients. Pathological complete response to neoadjuvant systemic therapy is a predictive factor consistent with a positive prognosis which can be accurately determined by percutaneous vacuum aspiration biopsy.&#x0D; AIM: To evaluate the amount of surgery in the group of patients with triple-negative and HER2-positive early breast cancer whose complete pathologic response was confirmed by vacuum aspiration biopsy and who did not undergo standard surgery.&#x0D; MATERIALS AND METHODS: The following single-centre study has been conducted in the Russian Federation. Women aged 18 years old and older with unicentric (cT1-2N0-1M0 by classification TNM) triple-negative or HER2-positive breast cancer with complete clinical response after neoadjuvant systemic therapy according to imaging diagnostic methods. The patients underwent vacuum aspiration biopsy on the mammary gland under ultrusound control with standard amount of surgical intervention on the axillary region. In case when no invasive or in situ disease was detected, no further breast surgery was performed and the patients underwent standard radiation therapy. The survival with no tumor relapse in the ipsilateral mammary gland was assessed as the primary endpoint. The study is registered on сlinicaltrials.gov, NCT04293796.&#x0D; RESULTS: Between June 2020 and May 2022, twenty-seven (84.4%) patients (all women; mean age 47.5 (3268) years) were enrolled in the study and underwent visually controlled vacuum aspiration biopsy. The average initial tumor size was 20.5 (735) mm. 7 (25.9%) patients initially had metastases in the axillary lymph nodes confirmed by puncture biopsy; 15 (55.6%) patients had HER2-positive breast cancer, and 12 (44.4%) had triple-negative breast cancer. A study of vacuum aspiration biopsy samples showed that 6 (22.2%) patients had a residual tumor, and 21 (77.8%) patients achieved complete pathologic response (95% confidence interval 53.2 to 81.4). At a median follow-up of 12.4 months, there were no tumor relapses in the ipsilateral mammary gland in 21 patients with complete pathologic response confirmed by vacuum aspiration biopsy after neoadjuvant systemic therapy, as well as other relapses or progression of the disease.&#x0D; CONCLUSIONS: The patients with a complete pathologic response, which is confirmed by the vacuum aspiration biopsy method, who refused to perform surgery on the mammary gland do not demonstrate worse results with a short period of observation. However, additional prospective clinical studies are needed.

Combinatory analysis of immune cell subsets and tumor-specific genetic variants can predict clinical response to PD-1 blockade for non-small cell lung cancer patients

Abstract Blockade of PD-1/PDL1 (PD-1 blockade) with antibodies has revolutionized treatment options for non-small cell lung cancer (NSCLC) patients with tumors without targetable mutations. The benefit of PD-1 blockade is limited only to a subset of the patients. This study aims to identify biological markers of clinical response in a discovery cohort (n=15) of patients early during treatment to distinguish responders from nonresponders using immunological and genetic markers. Immune subsets identified in the blood are characterized to establish a panel of immune markers that could distinguish the two. Blood drawn from NSCLC patients before and after PD-1 blockade was analyzed by clinical flow cytometric assay for changes in the frequencies and concentration of immune cell populations. Next generation sequencing was performed on the extracted DNA from archival tumor biopsies from the same patients. irRECIST criteria was used to evaluate the clinical responses with cut-off at 10 months. Responders had a significantly increased frequency of activated effector memory CD4 &amp; CD8 T cells &amp; decreased frequency of central memory CD4 &amp; CD8 T cells in circulation post-treatment compared to pre-treatment. In a separate cohort we validate initial findings in a cohort of n=29 &amp; observe that effector memory CD8 T cells in responders produced high TNFα at pretreatment. Pathogenic &amp; likely-pathogenic mutations in TP53, KRAS, KEAP1, NOTCH-1 and STK11 in the patients that responded to PD-1 blockade are observed. A multivariate analysis combining immune and genetic parameters could discriminate responders from non-responders. We report that combined analyses of selected immune cell &amp; genetic parameters could predict early clinical response to PD-1 blockade.

Abstract 2155: Joint modeling of safety and peripheral mode-of-action (MoA) biomarkers to support RP2D identification in Phase 1 study of SAR444245 (SAR’245) as monotherapy (mono) or combined with pembrolizumab (pembro) in patients with advanced solid tumors

Abstract Background: SAR’245 is a clinical-stage site-specific pegylated human IL-2 that blocks IL-2 alpha receptor binding but retains near-native binding affinity for beta/gamma IL-2 receptor subunits. When administered in preclinical models, a unique ‘T-cell remodeling’ MoA characterized by robust increase of CD8+Teff/CD4+Treg coupled with potent NK-cell activation/expansion was observed. Circulating tumor DNA (ctDNA) can be used as a non-invasive biomarker of early clinical response whilst overcoming challenges of obtaining repeat tumor biopsies from patients. Previously, we reported results of the Phase 1 HAMMER study (NCT04009681); herein, we describe an innovative integrative approach that considers peripheral key MoA biomarkers with objective response and dose-limiting toxicity (DLT) rate to help identify the recommended Phase 2 dose (RP2D) for SAR’245. Methods: SAR’245 was given IV as mono Q3W [Cohort B] or Q3W + IV pembro 200 mg Q3W/400 mg Q6W [Cohort C]. Joint modeling was carried out to account for the relationship between dose and 1) MoA biomarkers, and NK cells in blood measured by flow cytometry; 2) response surrogate biomarker: ctDNA measured by Guardant Omni 500 panel; and 3) DLTs. In the model, a latent variable was used to model correlation between DLT and the MoA or response surrogate biomarkers, Bayesian approach was used to derive posterior probabilities (PP) at each dose level of the target region (defined by &amp;gt;20% probability of fold change of biomarker values post-treatment above a predefined threshold and DLT rate &amp;lt;33%) and the PP of the overdose region (defined by DLT rate ≥33%). RP2D dose level was determined by maximizing the PP of target region among doses with PP of the overdose region probability &amp;lt;40%. Results: Samples from 35 subjects (Cohort B) and 34 subjects (Cohort C) were available. The results from SAR’245 mono suggests that the CD8/CD4 ratio and the concentrations of NK, CD8, and CD4 achieve maximum probability of reaching meaningful modulation (based on pre-defined threshold) around 32 ug/kg. When SAR’245 was combined with pembro, the results with PoM biomarkers showed the best performance at 24-32 µg/kg, while results with ctDNA showed the best results at 16-24 µg/kg. When all parameters were considered, either 24 or 32 µg/kg could serve as an adequate dose at Q3W scheduling. Conclusions: In early oncology studies, joint modeling using non-invasive biomarkers, including MoA and response biomarkers, and a safety profile can inform dose-response relationships and support RP2D selection. This innovative integrative modeling will guide clinical study design. Studies of SAR’245 that further explore the dosing and scheduling are on-going. Disclosures: This study was sponsored by Synthorx, a Sanofi company. Citation Format: Siqing Fu, Gerald S. Falchook, Minal Barve, Meredith McKean, Tira J. Tan, Charlotte Lemech, Cheng E. Chee, Neyssa Marina, Giovanni Abbadessa, Robin Meng, Federico Rotolo, Hong Wang, Jason Deng, Wenting Wang, Rui Wang, Tarek Meniawy. Joint modeling of safety and peripheral mode-of-action (MoA) biomarkers to support RP2D identification in Phase 1 study of SAR444245 (SAR’245) as monotherapy (mono) or combined with pembrolizumab (pembro) in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2155.

Combinatory analysis of immune cell subsets and tumor-specific genetic variants predict clinical response to PD-1 blockade in patients with non-small cell lung cancer.

Immunotherapy by blocking programmed death protein-1 (PD-1) or programmed death protein-ligand1 (PD-L1) with antibodies (PD-1 blockade) has revolutionized treatment options for patients with non-small cell lung cancer (NSCLC). However, the benefit of immunotherapy is limited to a subset of patients. This study aimed to investigate the value of combining immune and genetic variables analyzed within 3-4 weeks after the start of PD-1 blockade therapy to predict long-term clinical response. Blood collected from patients with NSCLC were analyzed for changes in the frequency and concentration of immune cells using a clinical flow cytometry assay. Next-generation sequencing (NGS) was performed on DNA extracted from archival tumor biopsies of the same patients. Patients were categorized as clinical responders or non-responders based on the 9 months' assessment after the start of therapy. We report a significant increase in the post-treatment frequency of activated effector memory CD4+ and CD8+ T-cells compared with pre-treatment levels in the blood. Baseline frequencies of B cells but not NK cells, T cells, or regulatory T cells were associated with the clinical response to PD-1 blockade. NGS of tumor tissues identified pathogenic or likely pathogenic mutations in tumor protein P53, Kirsten rat sarcoma virus, Kelch-like ECH-associated protein 1, neurogenic locus notch homolog protein 1, and serine/threonine kinase 11, primarily in the responder group. Finally, multivariate analysis of combined immune and genetic factors but neither alone, could discriminate between responders and non-responders. Combined analyses of select immune cell subsets and genetic mutations could predict early clinical responses to immunotherapy in patients with NSCLC and after validation, can guide clinical precision medicine efforts.

Relevance of Volumetric Parameters Applied to [68Ga]Ga-DOTATOC PET/CT in NET Patients Treated with PRRT

this study aims to explore the prognostic and predictive role of volumetric parameters on [68Ga]Ga-DOTATOC PET/CT in neuroendocrine tumors (NET) patients treated with peptide receptor radionuclide therapy (PRRT). We retrospectively evaluated 39 NET patients (21 male, 18 female; mean age 60.7 y) within the FENET-2016 trial (CTiD:NCT04790708). PRRT was proposed with [177Lu]Lu-DOTATOC alone or combined with [90Y]Y-DOTATOC. [68Ga]Ga-DOTATOC PET/CT was performed at baseline and 3 months after PRRT. For each PET/CT, we calculated SUVmax, SUVmean, somatostatin receptor expressing tumor volume (SRETV), and total lesion somatostatin receptor expression (TLSRE), as well as their percentage of changes (Δ), both for liver (_L) and for total tumor burden (_WB). Early clinical response (3 months after PRRT) and PFS were evaluated according to RECIST 1.1 and institutional NET board. Early clinical response identified 9 partial response (PR), 25 stable disease (SD), and 5 progressive disease (PD). Post-SRETV_WB and ΔSRETV_WB were progressively increased among response groups (p = 0.02 and p = 0.03, respectively). Likewise, median post-SRETV_L was significantly higher in PD patients (p = 0.03). SUVmax and TLSRE did not correlate with early clinical response. Median PFS was 31 months. Patients with ΔSRETV_WB lower than -4.17% as well as those with post-SRETV_WB lower than 34.8 cm3 showed a longer PFS (p = 0.006 and p = 0.06, respectively). Finally, multivariate analysis identified ΔSRETV_WB as an independent predictor for PFS. our results could strengthen the importance of evaluating the burden of disease on [68Ga]Ga-DOTATOC PET/CT in NET patients treated with PRRT.

Clinical significance of CA125 in unresectable pancreatic cancer treated with first-line chemotherapy.

745 Background: Serum CA125 is a potential biomarker for diagnosis of peritoneal metastasis in gastric cancer. However, its significance of pancreatic cancer (PC) has not been investigated. Therefore, we aimed to clarify association between serum CA125 and ascites burden, and its kinetics during first-line chemotherapy for PC. Methods: This multicenter retrospective study comprised PC patients who received FOLFIRINOX or gemcitabine plus nab-paclitaxel in first-line setting between Jan 2014 and Dec 2021. Patient background and treatment outcome was assessed in CA125 elevated and non-elevated group before chemotherapy. The CA125 kinetics after chemotherapy was calculated based on baseline and first measure of CA125. Further, the association between early CA125 change and clinical response during chemotherapy were evaluated based on optimal cut off value calculated receiver operating characteristic (ROC) curve analysis. Results: A total 109 patients from 3 hospitals were assessable. The overall survival (OS) was significantly shorter in elevated group than that in non-elevated group (median, 10.7 vs. 21.3 months, p = 0.0002). The median value of CA125 before chemotherapy was elevated according to ascites burden (Non, 36U/ml; mild, 173U/ml; moderate/severe, 575U/ml; p &lt; 0.0001). CA125 elevation, CA19-9 elevation, poor performance status and poor glasgow prognostic score were independent prognostic factors in multivariate analysis. After chemotherapy, the median first-time measure of CA125 was performed in day 41. Among patients with peritoneal dissemination, the median change of CA125 was correlated with clinical response (CR/PR, -0.55%/day; SD, -0.24%/day; PD, 3.35%/day, p = 0.004). After chemotherapy, first-time measure of CA125 was performed in a median of day 41. According to the ROC curve analysis, the optimal cut-off value of increase in CA125 for progressive disease was 1.56 %/day (specificity 94.1%, sensitivity 80%). The median PFS and OS were 1.4 and 6.6 months in increased group and 3.3 months and 14.0 months in non-increased group, respectively (p = 0.016 and p = 0.028). Conclusions: CA125 is considered a clinically useful marker in unresectable PC treated with first-line chemotherapy because CA125 above the ULN is a poor prognostic factor for OS and an increased CA125 can be an early predictor of progression in patients with peritoneal dissemination.

P680 A real-life experience of Crohn’s Disease Exclusion Diet use at disease onset and as an add-on therapy in pediatric Crohn’s disease

Abstract Background We aimed at appraising real-life efficacy of Crohn’s Disease Exclusion Diet (CDED) coupled with partial enteral nutrition (PEN) in inducing clinical and biochemical remission at disease onset and in patients with loss of response to biologics in a tertiary-level center. We also aimed at identifying early responders to this dietary regimen. Methods We gathered clinical, anthropometric and laboratory data of patients aged less then 18 years of age with a diagnosis of CD, who were consecutively treated with CDED coupled with PEN as main treatment for the induction of remission or in the setting of loss of response to other therapies. We collected data of patients who received CDED plus PEN from April 2019 to June 2022 at diagnosis, at the beginning of the dietary treatment, and at the phase 1. Patients who interrupted diet during follow-up were considered as treatment failures on an intent to treat basis. We compared groups using chi-square, Fisher’s exact test, Mann-Whitney U or related-samples Wilcoxon signed rank tests or McNemar’s test as appropriate. Results 47 patients were retrospectively identified. Table 1. summarizes clinical and biochemical characteristics at diagnosis and at CDED with PEN initiation. 24 (51.1%) patients started CDED as induction therapy at disease onset, whereas 23 (48.9%) of them received CDED with PEN as add-on therapy. 32/47 (68%) patients achieved clinical remission (wPCDAI &amp;lt; 12.5) at the end of phase 1, 16/24 patients (66.7%) who started CDED as induction therapy and 16/23 (69.5%) of those who started CDED as add-on, with no statistically significant difference among the two groups (p=1.00). Laboratory parameters significantly improved in both groups (Figure 1.). There were no statistically significant differences in clinical remission rates between patients with mild-to-moderate and severe disease at the end of phase 1 (25/35 vs 7/12, p=0.481). At disease onset, 14 patients added a concomitant treatment (11 patients added anti-TNF alpha, 3 patients added IMM and one patient added anti-TNF alpha + IMM) after a median time of 4 weeks (IQR: 3-5 weeks). 28 patients had clinical data gathered at week 3. Patients who achieved clinical response at week 3 (a change in wPCDAI &amp;gt; 12.5) were more likely to be in clinical remission at the end of phase 1 (17/20 vs 1/8, p&amp;lt;0.01), both in patients who started CDED at disease onset and in the add-on setting. Conclusion CDED with PEN confirmed its efficacy in a real-life setting, both as induction regimen and as add-on therapy, also in patients with clinically severe disease. Early clinical response predicts clinical remission at the end of phase 1, possibly allowing identification of dietary responsive disease. Table 1. Figure 1.