Overall Objective Response Rate Research Articles

Abstract PO3-06-09: A phase II study of nivolumab plus ipilimumab and androgen receptor antagonist bicalutamide to stimulate thymic T cell generation in HER2-negative metastatic breast cancer

Abstract Background: Systemic chemotherapy is used commonly in breast cancer and is associated with lymphopenia, potentially limiting efficacy of immune checkpoint blockade. The androgen receptor (AR) serves as a negative regulator of thymic function. AR antagonists, such as bicalutamide, may stimulate thymic production of naïve T-cells, which may help to restore lymphocyte diversity and augment immunotherapy response. The AR is expressed in 50% of hormone receptor negative (HR-) metastatic breast cancer (MBC) and >75% of HR+ MBC, and bicalutamide is clinically active with stable disease as best response. We hypothesize that bicalutamide could be combined with dual immune checkpoint blockade (anti-programmed death 1, nivolumab; plus anti-cytotoxic T-lymphocyte antigen 4, ipilimumab), stimulating T-cell production and resulting in durable clinical response. Methods: This is a phase II Simon 2-stage trial of nivolumab (240 mg IV q2w), ipilimumab (1 mg/kg IV q6w), and bicalutamide (150mg oral daily) for first- or second-line treatment of HER2-negative MBC (NCT03650894). The primary endpoint is iRECIST 24-week clinical benefit rate (CBR), evaluated separately for HR+ MBC (n=15) and AR+/HR- MBC (n=15). An optimum Simon 2-stage design (80% power, 5% one-sided alpha) is employed to evaluate an alternative hypothesis of >50% CBR compared to historical control of < 30% CBR for conventional chemotherapy, with expansion of each cohort planned if ≥6/15 responses are observed. Secondary outcomes include best overall objective response rate (ORR), progression-free and overall survival (PFS,OS), and safety. Exploratory endpoints include assessment of peripheral T-cell counts and T cell receptor excision circles (TREC PCR, Mayo Laboratories, a surrogate of thymic T-cell production) over time. Results: Durable responses were observed, with an ongoing complete response at 41+ months in a patient who discontinued due to toxicity (AR+/HR- cohort, PD-L1 CPS score 3%). Therapy was tolerated with a toxicity profile consistent with prior studies of ipilimumab & nivolumab, with five subjects (19%) requiring treatment discontinuation related to toxicity. Outcomes by cohort and PDL1 are summarized in Table 1. Using mixed effects linear models, therapy was associated with a significant expansion of CD8+ T cells (23/mcL/month, p< .01) but not CD3+ T cells (7/mcL/month, p=.59) or CD4+ T cells (4/mcL/month, p=.65). Baseline TREC counts were higher in younger participants (mean: < 50y 2156/mcL; 50-65y 961/mcL; >65y 311/mcL). TRECs did not increase globally, however TREC expansions were observed in several younger participants. Conclusions: The regimen of ipilimumab, nivolumab, plus bicalutamide is safe and clinically active in 1st/2nd-line HER2-negative MBC. Neither cohort crossed the Simon futility barrier for cohort expansion, however durable responses were observed including in PD-L1-negative patients, highlighting the unmet need for biomarkers to identify candidates for chemotherapy-sparing checkpoint blockade. Further research is indicated to evaluate the impact of AR antagonists on T-cell function and thymic stimulation in MBC. Acknowledgements: Drug and study support was provided by Bristol-Myers Squibb and The BMS International Immuno-Oncology Network (II-ON). Clinical outcomes XX XX HR: hormone receptor; AR: androgen receptor; CPS: PD-L1 combined positive score Citation Format: David Page, Alexander Hall, Krystle Collins, Nicole Moxon, Staci Mellinger, Tracy Kelly, Aysha Kelley, Nicole Fredrich, Amanda Seino, Gabriella Liberatore, Alison Conlin, Zheng Topp, Kelly Perlewitz, Sasha Stanton, Walter Urba, Yaping Wu, Maritza Martel, Zhaoyu Sun, Yoshinobu Kogushi, William Redmond, Tiffany Traina, Ayca Guculp. A phase II study of nivolumab plus ipilimumab and androgen receptor antagonist bicalutamide to stimulate thymic T cell generation in HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-09.

Neoadjuvant Immune Checkpoint Inhibitors in hepatocellular carcinoma: a meta-analysis and systematic review.

Neoadjuvant immunotherapy has demonstrated beneficial outcomes in various cancer types; however, standardized protocols for neoadjuvant immunotherapy in hepatocellular carcinoma (HCC) are currently lacking. This systematic review and meta-analysis aims to investigate the reliability of neoadjuvant immunotherapy's efficacy and safety in the context of HCC. A systematic search was conducted across PubMed (MEDLINE), EMBASE, the Web of Science, the Cochrane Library, and conference proceedings to identify clinical trials involving resectable HCC and neoadjuvant immunotherapy. Single-arm meta-analyses were employed to compute odds ratios and 95% confidence intervals (CIs). Heterogeneity analysis, data quality assessment, and subgroup analyses based on the type of immunotherapy drugs and combination therapies were performed. This meta-analysis is registered in PROSPERO (identifier CRD42023474276). This meta-analysis included 255 patients from 11 studies. Among resectable HCC patients, neoadjuvant immunotherapy exhibited an overall major pathological response (MPR) rate of 0.47 (95% CI 0.31-0.70) and a pathological complete response (pCR) rate of 0.22 (95% CI 0.14-0.36). The overall objective response rate (ORR) was 0.37 (95% CI 0.20-0.69), with a grade 3-4 treatment-related adverse event (TRAE) incidence rate of 0.35 (95% CI 0.24-0.51). Furthermore, the combined surgical resection rate was 3.08 (95% CI 1.66-5.72). Subgroup analysis shows no significant differences in the efficacy and safety of different single-agent immunotherapies; the efficacy of dual ICIs (Immune Checkpoint Inhibitors) combination therapy is superior to targeted combined immunotherapy and monotherapy, while the reverse is observed in terms of safety. Neoadjuvant immunotherapy presents beneficial outcomes in the treatment of resectable HCC. However, large-scale, high-quality experiments are warranted in the future to provide robust data support.

Hepatic arterial infusion chemotherapy combined with bevacizumab plus a PD-1 inhibitor for gallbladder cancer with hepatic oligometastasis: a real-world study.

Gallbladder cancer (GBC) is different from other biliary tract cancers in terms of molecular phenotype and microenvironment. Specific treatments for GBC need to be urgently explored. This study preliminarily investigated the clinical value of hepatic artery infusion chemotherapy (HAIC) combined with bevacizumab plus a programmed death receptor-1 (PD-1) inhibitor for treatment of GBC with hepatic oligometastasis. We retrospectively collected data on GBC patients with hepatic oligometastasis, who received this combination therapy. The clinical data, conversion rate, treatment response, adverse events (AEs), and short-term survival were summarized. The responses of primary gallbladder lesions and hepatic metastasis, and their effect on prognosis, were investigated. A total of 27 patients were included in the analysis. No grade 4 AEs were observed. The overall objective response rate (ORR) was 55.6% and the disease control rate (DCR) was 85.2%. Median overall survival (OS) time was 15.0 months and the 1-year survival rate was 64.0%. Median progression-free survival (PFS) time was 7.0 months and the 1-year PFS rate was 16.2%. Six patients (22.2%) were successfully converted to resection. Compared with primary gallbladder lesions, it appeared more difficult for patients with hepatic metastasis to achieve remission (ORR: 40.7% vs. 77.8%; P=0.012), but its response appeared to be closely related to the prognosis [median OS: 16.0 months in the complete response (CR) or partial response (PR) group vs. 11.0 months in the stable disease (SD) or progressive disease (PD) group, P=0.070; median PFS: 12.0 months in the CR or PR group vs. 6.5 months in the SD or PD group, P<0.001]. Preoperative CA19-9 of >1,900 U/mL and >5 cm metastatic lesions were associated with an unsatisfactory response, whereas a significant decrease of 18F-fluorodeoxyglucose (18F-FDG) uptake may be a marker of tumor remission. The combination of HAIC, a PD-1 inhibitor, and bevacizumab shows potential for advanced GBC with hepatic oligometastasis. The therapeutic response of hepatic metastasis had a greater influence on prognosis than that of primary gallbladder lesions.

Clinical benefit analysis of PD-1 inhibitors in patients with advanced, recurrent or metastatic cervical cancer: a meta-analysis and systematic review.

This study aims to comprehensively evaluate the efficacy and safety of programmed cell death protein-1 (PD-1) in patients with advanced, recurrent, or metastatic cervical cancer (ARMCC) and identify the population that may benefit the most. We conducted a search of PubMed, EMBASE, and the Cochrane Collaboration Library from their inception to September 2023. We extracted and analyzed the results related to the efficacy and safety of PD-1 in patients with ARMCC. The primary endpoints included the overall objective response rate (ORR) and adverse events (AEs), while the secondary endpoints encompassed the 1-year overall survival (OS) rate, 1-year progression-free survival (PFS) rate, as well as OS and PFS. We used a random effects model to conduct a meta-analysis on single-group rates, and the Mantel-Haenszel method was utilized to compare the ORR and the incidence of AEs. Our study included a total of 21 trials involving 2,097 patients. The ORR of the combination of PD-1 inhibitors with chemotherapy was 56.36%, the combination of PD-1 inhibitors with anti-angiogenic agents was 38.72%, the combination of PD-1 inhibitors with Cytotoxic T-lymphocyte antigen 4 inhibitors was 25.60%, and PD-1 inhibitor monotherapy was 15.99%. The subgroup analysis showed that the group of patients with squamous cell carcinoma (SCC) exhibited a significantly higher ORR compared to the non-SCC group in patients who received PD-1 inhibitors combined with other anti-tumor drugs (Odds Ratio =2.43, P=0.002). Additionally, the group of patients with a programmed death-ligand 1 combined positive score (PD-L1 CPS) ≥1 exhibited a significantly higher ORR compared to the PD-L1 CPS <1 group in patients who received PD-1 inhibitor monotherapy (OR=4.14, P=0.02). PD-1 inhibitor monotherapy or PD-1 inhibitors combined with chemotherapy did not significantly increase the incidence of all grades of adverse events (Relative Risk=0.99, p=0.788) or the incidence of serious adverse events (RR=0.99, p=0.788) compared to chemotherapy alone. PD-1 inhibitors demonstrate outstanding efficacy in the treatment of patients with ARMCC. Patients with SCC may benefit more from treatments including PD-1 inhibitors in combination with other anti-tumor drugs, and PD-L1 CPS ≥1 can be considered a favorable indicator of immune therapy response. Importantly, the use of PD-1 inhibitor monotherapy or PD-1 inhibitors in combination with chemotherapy did not lead to an increased incidence of AEs compared with chemotherapy alone, indicting safety during treatment. PROSPERO (CRD42023457945).

Transcriptional Profiling Associated with CD22 CAR T Cell Clinical Response in LBCL

Introduction We have previously presented outcomes of a phase 1 trial (NCT04088890) in which 38 patients with CAR19-refractory LBCL received a single infusion of a CD22-directed CAR T cell (CAR22) at either 1 (DL1) or 3 (DL2) million CAR+ cells/kg. The overall objective response rate (ORR) and complete response (CR) rate were 68% (95% confidence interval [CI], 51 to 83) and 53% (95% CI 36 to 69), respectively. The impact of CAR22 product characteristics on outcomes and CAR22 expansion is unknown and our objective is to identify CAR T cell intrinsic factors associated with treatment outcomes. Methods Comprehensive phenotyping and exhaustion profiling were performed on manufacturing samples during apheresis, enrichment, and final product harvest. Additionally, quantification of lymphocyte subsets (CAR+ and CAR-) in all patients was carried out using flow cytometry/qPCR on peripheral blood samples. For in-depth analysis, raw single-cell RNA-seq (scRNA-seq) data from cryopreserved aliquots of 14 CAR22 products was processed through the 10× Genomics platform. Results The OR (78% vs 66%) and CR rates (56% vs 52%) were similar between DL1 and DL2, and peripheral blood CAR+ T cells peaked at a median of 71 and 360 CAR+ T cells/mL at DL1 and DL2, respectively, at a median of 14 days (range, 7 to 22) post-infusion. Subjects with a response vs. those without a response (median 141 vs 9.2, P=0.0022); subjects with grade 2 or 3 CRS vs. those with grade 1 or no CRS (median 203 vs 46, P=0.026); and subjects who required treatment for IEC-HS vs. those who did not develop IEC-HS (median 1884 vs 90, p-value 0.0016) had significantly higher circulating CAR22 T-cells at peak expansion, as well as higher cumulative levels of CAR+ T cells measured by AUC over the first 28 days (Figure 1). Characterization by flow cytometry analysis identified a predominance of CD4+ CAR T cells in all CAR22 products. Despite this, CD8+ T-cells represented the majority of CAR+ T cells post-infusion. We obtained matched single-cell sequencing data from 14 products for transcriptome, surface protein expression, and TCR sequence. Analyzed were 242,571 cells, of which 141,152 expressed the CAR22 transgene. Products were representative of the study population in terms of age, sex, cell dose, adverse events, and clinical outcome. Higher TCR diversity was found in products of patients who achieved a CR. We applied the propeller method to calculate significant differences in cell type proportions related to response, performing transformation on cell type proportions using linear modelling, and found a significantly higher proportion of terminal effector memory cells (TEMRA) in the products of patients who progressed. Dividing our cohort into subgroups based on high percentage (≥median) or low percentage (&amp;lt;median) of CD4+ TEMRA cells in products by flow cytometry, there was a significantly better progression free survival in the latter. Differential gene expression analysis revealed that CAR + T cells in the products of patients achieving CR expressed higher levels of FOS and JUN, transcription factors of the AP-1 family (Figure 2). In contrast, cells from patients who progressed showed higher levels of multiple immunomodulatory killer cell immunoglobulin like receptors (KIRs). Discussion This study demonstrates that CAR T cell expansion correlates with clinical response and toxicities of the CAR22 therapy. However, little is known about the clonal composition of CAR22 products and how distinct transcriptional signatures in the CAR T products might affect cell performance in vivo. In this exploratory analysis, we identified an association TEMRA cells with poor response. In addition, we observed higher expression of FOS and JUN in CAR22 products of patients achieving CR. The classic AP-1 heterodimer c-Fos-c-Jun drives transcription of IL2 and has also been described to contribute to exhaustion resistance in CD19 targeting CAR T cells. This study identifies specific cell features that are associated with the clinical outcome CAR22 therapy, which has implications for optimizing CAR22 products for improved clinical outcomes. Further analyses are ongoing to examine the clonal dynamics of the CAR22 T cells in vivo by including patient samples at later timepoints to our scRNA-seq dataset.

RTID-01. A RANDOMIZED STUDY OF LOW-INTENSITY FOCUSED ULTRASOUND FOR BLOOD-BRAIN BARRIER DISRUPTION FOR BRAIN METASTASIS FROM NON-SMALL CELL LUNG CANCER (LIMITLESS)

Abstract BACKGROUND Blood-brain barrier disruption (BBBD) has been demonstrated, in preclinical models, to improve systemic drug delivery for BM. Low-intensity focused ultrasound (LIFU) with intravenously (IV) administered microbubble oscillators results in non-invasive BBBD, potentially permitting drug delivery. This randomized controlled trial (RCT) aims to determine the safety and efficacy of LIFU-mediated BBBD for NSCLC BM with immunotherapy. METHODS LIMITLESS is an ongoing prospective, multicenter, parallel-arm, open-label RCT that randomizes patients with NSCLC-BM on pembrolizumab monotherapy prescribed as per standard-of-care to LIFU plus pembrolizumab (arm 1) or pembrolizumab alone (arm 2) in 2:1 ratio. Included patients have age ≥18 years, normal organ function, KPS≥70, EGFR- and ALK-negative primary tumor, and ≤3 BM, with ≥1 BM meeting measurable disease RANO-BM criteria. Patients on both arms receive standard-of-care therapy, while those on arm 1 also undergo LIFU before each dose of pembrolizumab (200 mg IV every 3 weeks). These patients undergo pre-treatment MRI brain, followed by IV administration of oscillating microbubbles for enhanced sonication. MR-guided BBBD is then performed using 220 kHz LIFU device with real-time acoustic feedback. Pembrolizumab is infused immediately thereafter, and repeat MRI done confirming BBB closure each cycle. Primary study endpoint is overall objective response rate (ORR) at 6 months as per RANO-BM criteria. Using a Bayesian design, a superior ORR of 60% is assumed for the LIFU arm versus 30% in the control arm for N = 96, 64 subjects in LIFU and 32 in control arm, for 80% power, with alpha = 0.05. For upper-bound estimate ORR of 45% in LIFU arm and 30% in control arm, the study needs N = 369 subjects; 246 in the LIFU arm and 123 in the control arm. Secondary outcomes are the best overall response rate and median time-to-response. Exploratory outcomes are median PFS, OS, intracranial PFS, extracranial PFS, and quality of life. Clinical trial information: NCT05317858.

P07.13.B A RANDOMIZED STUDY OF LOW-INTENSITY FOCUSED ULTRASOUND FOR BLOOD-BRAIN BARRIER DISRUPTION FOR BRAIN METASTASIS FROM NON-SMALL CELL LUNG CANCER (LIMITLESS)

Abstract BACKGROUND The blood-brain barrier (BBB) limits the efficacy of systemic therapies for brain metastases (BM), for which non-small cell lung cancer (NSCLC) is the most common etiology. BBB disruption (BBBD) has been demonstrated, in preclinical models, to improve systemic drug delivery for BM. Low-intensity focused ultrasound (LIFU) results in non-invasive BBBD synergistically with intravenously (IV) administered microbubble oscillators. This randomized controlled trial (RCT) aims to determine the safety and efficacy of LIFU-mediated BBBD for NSCLC BM with immunotherapy. METHODS LIMITLESS is an ongoing prospective, multicenter, parallel-arm, open-label RCT that randomizes patients with NSCLC BM on pembrolizumab monotherapy prescribed as per standard-of-care to LIFU plus pembrolizumab (arm 1) or pembrolizumab alone (arm 2) in 2:1 ratio. Included patients have age ≥18 years, normal organ function, Karnofsky Performance Status ≥70, EGFR- and ALK-negative primary tumor, and ≤3 BM with ≥1 BM meeting measurable disease criteria as per response assessment in neuro-oncology for BM (RANO-BM). Patients on both arms receive standard-of-care therapy, while those on arm 1 also undergo LIFU before each dose of pembrolizumab (200 mg IV every 3 weeks). These patients undergo pre-treatment MRI brain, followed by IV administration of oscillating microbubbles for enhanced sonication. MR-guided BBBD is then performed using a 220 kHz LIFU device with real-time acoustic feedback for maintaining effective cavitation. Pembrolizumab is infused immediately thereafter, and a repeat MRI is done 24-48 hours later to confirm the closure of BBB each cycle. The primary study endpoint is the overall objective response rate (ORR) at 6 months, as assessed using RANO-BM criteria. Using a Bayesian design for power analysis, a superior ORR of 60% is assumed for the LIFU arm versus 30% in the control arm for a total sample size of N=96, 64 subjects in LIFU and 32 in the control arm, for 80% power using a two-sided chi-square test with an alpha of 0.05. For the upper-bound estimate ORR of 45% in the LIFU arm and 30% in the control arm, the study needs N=369 subjects; 246 in the LIFU arm and 123 in the control arm. The secondary outcomes are the best objective response rate and median time-to-response per treatment arm. The exploratory outcomes are median progression-free survival (PFS), overall survival (OS), median intracranial PFS, median extracranial PFS, and quality of life. RESULTS Patient enrollment commenced in 2022. CONCLUSION Findings from this trial will be critical to liquid biopsy in brain metastases (Clinical trial information: NCT05317858).

Phase 1 study of vibecotamab identifies an optimized dose for treatment of relapsed/refractory acute myeloid leukemia

AbstractAcute myeloid leukemia (AML), an aggressive malignancy with unmet medical need, lacks immunotherapeutic options. CD123, the cellular receptor for interleukin-3, expressed in AML is an attractive target for tumor-specific therapy. Vibecotamab (XmAb14045), a humanized bispecific antibody, monovalently binds both CD3 and CD123 to recruit cytotoxic T cells to kill CD123+ tumor cells. This phase 1 study’s primary objectives were safety and tolerability and identification of a maximum tolerated dose/recommended dose for use as monotherapy in patients with relapsed/refractory AML. Identification of a recommended phase 2 vibecotamab dose comprised 3 step-up doses (Week 1), which were noted to reduce cytokine response syndrome (CRS), followed by weekly dosing (1.7 μg/kg, Cohort -1D). In 16 of 120 patients, at least 1 treatment-emergent adverse event was classified as a dose-limiting toxicity. CRS, the most common adverse event (59.2%), managed with premedication, were mostly ≤grade 2. A secondary objective was assessment of efficacy in patients with CD123-expressing leukemias. A total of 10 of 111 (9.0%) efficacy-evaluable patients with AML achieved an overall response of morphologic leukemia-free state or better with an overall objective response rate (ORR) of 9.0%. Response was only observed in patients receiving a target dose of 0.75 μg/kg or higher (n = 87) in which the efficacy-evaluable ORR was 11.5%. Response was associated with lower baseline blast counts in blood and bone marrow (<25%) suggesting potential benefit. This trial was registered at www.clinicaltrials.gov as #NCT02730312.

[Efficacy and safety evaluation of immunotherapy combined with targeted therapy as second-line treatment in patients with metastatic non-clear cell renal cell carcinoma].

Objective: This study aimed to evaluate the efficacy and safety of programmed death-1 (PD-1) inhibitor combined tyrosine kinase inhibitor (TKI) therapy versus TKI monotherapy as the second-line regimen for patients with metastatic non-clear cell renal carcinoma (nccRCC) who failed first-line TKI therapy. Methods: The clinicopathological data of 67 patients with metastatic nccRCC who failed first-line TKI therapy between October 2011 and September 2020 were retrospectively analyzed, including 22 patients who received TKI monotherapy and 45 patients who received TKI plus PD-1 inhibitor as the second-line therapy. The efficacy was assessed according to Response Evaluation Criteria in Solid Tumors version 1.0/1.1 (RECIST 1.0/1.1), the Kaplan-Meier method was used to plot the survival curves, and the Log rank test was used to analyze the differences in the survival between the two groups. Treatment-related adverse events (AEs) after treatment were observed in both groups. Results: The overall objective response rate (ORR) and disease control rate (DCR) were 37.3% (25/67) and 56.7% (38/67), respectively. The overall second-line progression-free survival (PFS) was 7.7 months and Overall Survival (OS) was 25.2 months. The ORR and DCR of patients in the combination therapy group were 48.9% (22/45) and 71.1% (32/45), respectively, which were significantly improved compared with the TKI monotherapy group [13.6% (3/22) and 27.3% (6/22), respectively] (P=0.007 and P=0.001, respectively). The median PFS of 9.2 months for second-line treatment was longer in patients in the combination therapy group than in the TKI monotherapy group (5.2 months, P=0.001), but the median OS was not statistically different between the two groups (28.2 months vs 20.8 months, P=0.068). Common treatment-related AEs included hypertension, diarrhea, fatigue, stomatitis, hand-foot syndrome, and hypothyroidism. The incidence of hypothyroidism was higher in the combination therapy group [40.0% (18/45)] than in the TKI monotherapy group [22.7% (5/22), P=0.044]; the incidence of other treatment-related AEs between the two groups were not statistically significant (all P>0.05). Conclusion: Immune-targeted combination therapy was more effective than TKI monotherapy alone and was well tolerated in the treatment of metastatic nccRCC patients who failed first-line TKIs.

Efficacy of apatinib combined with temozolomide in the treatment of recurrent high‑grade glioma: A meta‑analysis.

Recurrent high-grade glioma is a refractory disease, and its prognosis is poor. Although the treatment of apatinib combined with temozolomide provides improved efficacy and is able to prolong survival, this conclusion has been based on small samples. In order to clarify this treatment's efficacy, a meta-analysis was performed in the present study. Different databases were screened and finally, 10 studies were included, comprising 357 patients with recurrent high-grade gliomas. The efficacy and prognosis were analyzed using Stata software. The results indicated that the overall objective response rate (ORR) and disease control rate (DCR) of apatinib combined with temozolomide were 0.36 (95% CI, 0.26-0.46) and 0.86 (95% CI, 0.82-0.89), respectively. Subgroup analysis indicated that the overall ORR was 0.43 (95% CI, 0.29-0.57) and 0.26 (95% CI, 0.14-0.38), and the DCR was 0.89 (95% CI, 0.85-0.93) and 0.76 (95% CI, 0.69-0.84) in the treatment of apatinib with temozolomide dose-dense group and the conventional-dose group (5/28 regimen), respectively. Further prognostic analysis indicated that the median overall survival of patients with high-grade glioma treated with apatinib combined with temozolomide was 8.21 months (95% CI, 7.20-9.22 months) and the median progression-free survival was 5.45 months (95% CI, 4.53-6.37). Analysis of the publication bias of the effect size revealed that there was bias in the DCR, while no bias was found in the remaining effect size (ORR, median overall survival and median progression-free survival). After correction by the trim-and-fill method, bias was indicated to have no significant impact on the results. In conclusion, apatinib combined with temozolomide has the effect that, compared with traditional Bevacizumab treatment, it can improve the efficacy in the treatment of recurrent high-grade glioma and improve prognosis. When combining with dose-dense temozolomide, the effect may be better than that of the conventional 5/28 regimen.

Ramucirumab plus irinotecan / leucovorin / 5-FU versus ramucirumab plus paclitaxel in patients with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction, who failed one prior line of palliative chemotherapy: the phase II/III RAMIRIS study (AIO-STO-0415)

BackgroundPaclitaxel in combination with ramucirumab is the standard of care second-line therapy in gastro-esophageal adenocarcinoma (GEA). As the number of taxane pretreated patients in the perioperative or first-line setting is increasing, it is unknown whether these patients benefit from re-applying a taxane in using the combination of paclitaxel and ramucirumab. Furthermore, the rates of neurotoxicity with first-line FOLFOX or FLOT range from 30%–70%, making second-line taxane‐containing therapy less suitable to a meaningful portion of patients. This patient group is likely to benefit from a taxane-free second-line chemotherapy regimen, such as FOLFIRI and ramucirumab (FOLFIRI-Ram). Therefore, the RAMIRIS phase III trial evaluates the effects of the regimen of FOLFIRI-Ram in the second-line treatment after a taxane-based chemotherapy in patients with advanced GEA.MethodsThe RAMIRIS trial is a randomized, open-label, multicenter phase II/III study comparing treatment of FOLFIRI-Ram (arm A) with paclitaxel and ramucirumab (arm B). The Phase II is already closed with 111 enrolled patients. In the phase III, 318 taxane-pretreated patients with advanced GEA will be recruited and randomized 1:1 to FOLFIRI (5-FU 2400 mg/m2 over 46 h i.v., irinotecan 180 mg/m2 i.v.; 5-FU 400 mg/m2 bolus; leucovorin 400 mg/m2 i.v.; on day 1 and 15, q28) with ramucirumab 8 mg/kg every two weeks (Arm A) or paclitaxel 80 mg/m2 (days 1, 8, 15, q28) with ramucirumab 8 mg/kg every two weeks (Arm B). The primary endpoints are overall survival (OS) and objective overall response rate (ORR). Secondary endpoints are progression-free survival (PFS), disease control rate and safety and quality of life as assessed by EORTC-QLQ-C30 questionnaire.DiscussionThe already completed RAMIRIS phase II demonstrated feasibility and efficacy of FOLFIRI-Ram. Especially docetaxel-pretreated patients seemed to markedly benefit from FOLFIRI-Ram, with favorable response- and PFS rates and lower toxicity. This offers a rationale for the phase III trial. If the RAMIRIS III trial transfers and confirms the results, they will affect the current treatment guidelines, recommending the combination therapy of FOLFIRI-Ram for taxane-pretreated patients with advanced GEA.Trial registrationNCT03081143 Date of registration: 13.11.2015

Efficacy and safety of camrelizumab combined with apatinib in the treatment of advanced gastric cancer: Preliminary results from a multicenter, prospective study.

e16035 Background: There is an urgent need to find new therapeutic drugs/regimens for advanced gastric cancer. Camrelizumab combined with apatinib and chemotherapy has shown a high objective response rate and survival benefit in the first- and second-line treatment of advanced gastric cancer. Therefore, we conducted a prospective, observational study to analyze the efficacy and safety of camrelizumab combined with apatinib and chemotherapy in the first- and second-line treatment of advanced gastric cancer. Methods: This was a multicenter, observational study enrolling patients aged ≥ 18 years with an ECOG PS of 0-2 and pathologically or histologically confirmed advanced gastric cancer. Results: By January 9, 2023, 207 patients with advanced gastric cancer from 32 centers were enrolled. Most patients were male (138 [66.7%]), stage IV (151 [72.9%]), and ECOG PS of 1 (145 [70.0%]) with a median age of 66 years. The degree of differentiation was mainly moderate and low (155 [74.9%]). 109 patients (52.7%) had a surgical history of the primary lesion, 123 (59.4%) had previously received chemotherapy, and 115 (55.6%) had received COVID-19 vaccine. The first-line treatment included camrelizumab plus chemotherapy for 4-6 cycles followed by apatinib in 68 patients (32.9%), and camrelizumab plus chemotherapy and apatinib in 51 (24.6%). Second-line treatment included camrelizumab plus apatinib for 35 patients (16.9%), chemotherapy and apatinib for 44 (21.3%), and other treatments for 9 (4.3%). Clinical efficacy was evaluated in 52 patients. There were 20 patients with partial response, 26 with stable disease, and 6 with progressive disease. The overall objective response rate (ORR) was 38.46% and disease control rate (DCR) was 88.46%. The ORR and DCR in the first-line setting were 50.00% and 100.00%, and ORR and DCR in the second-line setting were 16.67% and 66.67%. Furthermore, the ORR was 40.63% and the DCR was 90.63% in patients vaccinated against COVID-19 compared to 40.00% and 85% in unvaccinated patients. The median PFS and OS have not been reached. The incidence of adverse events (AEs) was 80.4% and the incidence of grade≥3 AEs was 3.5%. The most common AEs were reactive cutaneous capillary endothelial proliferation (71.3%), nausea (51.0%), leukocyte reduction (38.46%), and hypertension (13.3%). Conclusions: In this real-world study of gastric cancer, the first-line treatment showed good efficacy, suggesting early administration with combination treatment may bring more benefits to the patients. Additionally, COVID-19 vaccination did not affect the efficacy of combination treatment. Further validation of these preliminary results is warranted. Clinical trial information: ChiCTR2200059650 .

BRENTUXIMAB VEDOTIN IN COMBINATION WITH CHEMOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED CD30‐POSITIVE PERIPHERAL T‐CELL LYMPHOMAS: REAL‐WORLD DATA

Background: Based on the results of ECHELON-2 trial, Brentuximab vedotin (BV) in combination with cyclophosphamide, doxorubicin and prednisone (CHP) has been approved by EMA for the treatment of newly diagnosed systemic anaplastic large cell lymphoma (ALCL) and become the standard of care for this patient population. In Czech Republic, BV plus CHP is approved as 1st line treatment for CD30-positive peripheral T-cell lymphomas (PTCL), including non-ALCL PTCL since 8/2020. The aim of this analysis is to provide real world data with this combination. Methods: Using the prospective observational NiHiL project (NCT03199066), we identified patients (pts) ≥ 18 years of age with histologically confirmed CD30+ PTCL (diagnosed between August 2020 to October 2022), who received BV in combination with chemotherapy as 1st line treatment. Results: A total of 63 pts were recruited; 31 (49%) had ALCL (12 ALK+, 19 ALK-) and 32 (51%) had non-ALCL PTCL (16 with PTCL NOS, 14 with AITL, and 2 with EATL). Median age was 60 years (range; 19-82). Most pts showed adverse clinical features at lymphoma diagnosis, including Ann Arbor stage III-IV (n = 46; 73%) or elevated LDH (n = 34; 54%). Of note, 18 (29%) pts had ECOG performance status ≥ 2 (incl. 6 pts ECOG 3 and 1 pt ECOG 4). By IPI, 16 (25%), 18 (29%), 12 (19%), and 17 (27%) pts belonged to low, low-intermediate, high-intermediate, and high-risk groups, respectively. The most common chemotherapy backbone was CHP administered in 45 (71%) pts, followed by CHP + etoposide administered in 13 (21%) pts. Five (8%) pts received attenuated regimen. Nine (14%) pts underwent pre-planned consolidative autologous stem cell transplant. Sixty (95%) pts received G-CSF prophylaxis. The most common grade ≥3 adverse events were neutropenia (49%), anaemia (30%), febrile neutropenia (19%), thrombocytopenia (19%), and infections (18%). Neuropathy (all grades) occurred in 21 pts (33%); grade 3 neuropathy in 3 pts (5%). Grade 5 AE occurred in 2 (3%) pts, sepsis in both cases. Out of 63 there were 56 (89%) pts evaluable for response (PET/CT) at the time of database lock. The overall objective response rate (ORR) was 80% with 63% complete response (CR). The ORR/CR rates in ALCL (n = 26) versus non-ALCL (n = 30) pts were 89%/73% versus 73%/53%, respectively. The median follow-up of surviving pts is 16.6 months (range; 4.3- 31.3). The overall 18-months PFS and OS probability were 61.8% and 73.7%, respectively (Figure 1). By lymphoma subtype, the 18-months PFS and OS probability were 77.6% and 83.5% in ALCL and 50.3% and 65.9% in non-ALCL, respectively (Figure 1). Evaluation of the relationship between % of CD30+ neoplastic cells and clinical outcome is ongoing. The research was funded by: The study is supported by the Cooperation Program, research area “Oncology and Haematology” and NU20-03-00253 and NU22-03-00370. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Combination Therapies Conflicts of interests pertinent to the abstract A. Sykorova Other remuneration: ROCHE, GILEAD, TAKEDA H. Mocikova Consultant or advisory role Takeda, Roche, Astra Zeneca, Janssen, Abbvie D. Belada Other remuneration: Roche, Gilead Sciences M. Trneny Consultant or advisory role Takeda Honoraria: Takeda

Initial efficacy and safety of RP1 + nivolumab in patients with anti–PD-1–failed melanoma from the ongoing phase 1/2 IGNYTE study.

9509 Background: Patients (pts) with melanoma who progress on anti–PD-1 therapy (anti–PD-1–failed) have limited treatment options. RP1 is an HSV-1–based oncolytic immunotherapy expressing human GM-CSF and a fusogenic protein (GALV-GP-R−). Here, we present data from the first 75 pts enrolled into the registration-directed (R-D) cohort in anti–PD-1–failed melanoma (target enrollment N = 125) from the phase 1/2 IGNYTE study (NCT03767348). Methods: Pts must have locally advanced or metastatic cutaneous melanoma with ≥1 measurable and injectable tumor (≥1 cm) and confirmed progressive disease (PD) on 2 assessments ≥28 days apart while on ≥8 consecutive weeks of anti–PD-1 ± anti–CTLA-4 therapy, with anti–PD-1 being the last treatment received. Pts on prior adjuvant anti–PD-1 therapy must have had PD confirmed by biopsy while on adjuvant therapy. RP1 is initially given intratumorally at 106 PFU/mL and then every 2 weeks (Q2W) at 107 PFU/mL for ≤8 total cycles (≤10 mL/dose) combined with nivolumab (nivo; cycles 2–8, 240 mg IV); pts then receive nivo alone (240 mg Q2W or 480 mg Q4W IV) for ≤2 years, with the option to reinitiate RP1 if specified criteria are met. Results: A total of 91 pts are included in this analysis (initial melanoma cohort, 16 pts; R-D cohort, 75 pts; data cut: Dec 30, 2022). The overall objective response rate (ORR) was 37.4% (initial cohort, 37.5%; R-D cohort, 37.3%) and 18.7% of pts achieved complete response (CR; Table). The response rates seen were also encouraging when evaluated by prior anti–PD-1 therapy setting and disease stage (Table). Responses were seen in uninjected lesions in most responding patients, including in pts with bulky and visceral disease. The majority of responses were observed in pts with PD-L1–negative tumors at baseline (17 of 52 pts with PD-L1–negative tumors responded, compared to 15 of 26 pts with PD-L1–positive tumors, and 2 of 13 pts for whom PD-L1 status was unknown). 85.3% of responses were ongoing 3.7–36.6 months from initiating therapy. Most treatment-related adverse events (TRAEs) were Grade 1–2 with the most common (&gt;20%) being fatigue, chills, pyrexia, and nausea. Conclusions: The initial data from this expanded cohort show that RP1 + nivo provides durable and clinically meaningful antitumor activity in pts with anti–PD-1–failed melanoma. Responses were observed in both injected and uninjected lesions, including visceral lesions. The combination continues to be well tolerated, with mostly on-target TRAEs. Additional and updated data will be presented. Clinical trial information: NCT03767348 . [Table: see text]

OFF‐THE‐SHELF CD30.CAR‐MODIFIED EPSTEIN‐BARR VIRUS‐SPECIFIC T CELLS (CD30.CAR EBVSTS) PROVIDE A SAFE AND EFFECTIVE THERAPY FOR PATIENTS WITH HODGKIN LYMPHOMA (HL)

Off-the-shelf allogeneic T-cell therapies face the major challenges of graft-versus-host disease (GVHD) and graft rejection mediated by host and recipient alloreactive T cells, respectively. To address GVHD, we are using Epstein-Barr Virus-specific T cells (EBVST), which are virus specific rather than allo-specific and have not produced GVHD in over 300 allogeneic recipients. To prevent graft rejection, we modified the EBVST with a chimeric antigen receptor (CAR) targeting CD30, an antigen that is upregulated on allo-activated T-cells, which will consequently become targets for CD30.CAR EBVST. Hence, CD30.CAR EBVST can kill both CD30+ lymphoma cells and alloreactive T cells through their CAR, and may be boosted in vivo in EBV+ recipients via their native TCR. We are evaluating this approach in a phase 1 trial (NCT04288726) in patients with CD30+ lymphoma. We generated a bank of 7 CD30.CAR EBVST products by stimulating PBMC from healthy donors with overlapping EBV peptide mixtures followed by retroviral transduction with a 2nd generation, CD28-containing CD30.CAR. We have treated 16 patients (median age 36, range 22–53) with relapsed or refractory HL. Patients had undergone a median of 5 (range 3–7) prior lines of treatment. Escalating doses of 4 × 107 − 8 × 108 (DL1–4) CD30.CAR EBVST were infused after lymphodepletion. The frequency of CD30.CAR EBVST was measured by real time qPCR for the transgene in blood. Changes in the frequency of T-cells responding to EBV or tumor-associated antigens (epitope spreading) were measured by IFNɣ ELISpots. Clinical responses were assessed per Lugano criteria by PET/CT scans performed 4–8 wks post infusion. CD30.CAR EBVST were well tolerated, with no GVHD and only two patients having reversible grade 4 cytopenia. Five patients at DL3–4 had grade 1 cytokine release syndrome (CRS), but all resolved without treatment. Of the 16 patients treated, 6 had partial responses (PR) and 6/13 patients at DL2–4 had complete responses (CR), giving an overall objective response rate (ORR) of 75%. Despite these remarkable responses, qPCR for the CD30.CAR transgene showed near background levels by wk 1 post infusion. Although this could mean that CAR-T are quickly eliminated by alloreactive T-cells, additional infusions from the same donor product into the same patient can be associated with response (Figure 1); an alloreactive response would be anticipated to be amplified after each infusion and preclude additional responses. We are therefore analyzing tumor biopsy samples to determine the presence of CD30.CAR EBVST at tumor sites and characterize their phenotype for functionality. The research was funded by: Leukemia and Lymphoma Society SCOR (Heslop) and Tessa Therapeutics (Rooney/Ramos) through a grant to Baylor College of Medicine. Keywords: cellular therapies, Hodgkin lymphoma Conflicts of interests pertinent to the abstract C. A. Ramos Consultant or advisory role: Novartis, Genentech, CRISPR Therapeutics Research funding: Tessa Therapeutics, Athenex Therapeutics Other remuneration: Royalties: Tessa Therapeutics D. H. Quach Research funding: Tessa Therapeutics P. D. Lulla Research funding: Marker Therapeutics, Allovir R. H. Rouce Consultant or advisory role: Pfizer, Novartis Honoraria: Novartis, Medline Plus Research funding: Tessa Therapeutics B. J. Grilley Consultant or advisory role: Allovir, Marker Therapeutics, Tessa Therapeutics, Lokon Pharma, March Bio and Proxima Clinical Research Stock ownership: Allovir, QBRegulatory LLC N. Lapteva Consultant or advisory role: Tessa Therapeutics Research funding: Tessa Therapeutics M. K. Brenner Employment or leadership position: Founder Member Marker Therapeutics Consultant or advisory role: Tessa Therapeutics, Marker Therapeutics, Allogene, Walking Fish, Athenex, Turnstone Biologics, Posedia, Tscan, Bluebird Bio, Adaptimmune Therapeutics, Adintus, Onkimure, Triumvira Immunologics, Bellicum Pharmaceuticals, Memgen LLC, Brooklyn Immunotherapeutics, Coya, Astrazeneca Pharmaceuticals Stock ownership: Allovir, Marker Therapeutics, Tessa Therapeutics, Turnstone, Bluebird Bio, Allogene, Walking Fish, AlloVir, Tessa, Tscan Other remuneration: Royalties: Takeda, Bellicum, Marker Therapeutics H. E. Heslop Consultant or advisory role: Gilead Biosciences, Novartis, Tessa Therapeutics, Marker Therapeutics, Kiadis, PACT Pharma, Mesoblast, Ankyra Therapeutics Stock ownership: Allovir, Marker Therapeutics, Fresh Wind Biotechnologies, CoRegen Inc. Research funding: Tessa Therapeutics, Athenex Therapeutics C. M. Rooney Consultant or advisory role: Tessa Therapeutics, Marker Therapeutics, Cell Genix Stock ownership: Allovir, Marker Therapeutics Research funding: Tessa Therapeutics Other remuneration: Royalties: Takeda, Marker, Allovir, Bellicum

Hepatic arterial infusion chemotherapy combined with anti-PD-1/PD-L1 immunotherapy and molecularly targeted agents for advanced hepatocellular carcinoma: a real world study.

Molecular targeted therapy combined with immunotherapy significantly improves the prognosis of patients with advanced liver cancer. Additionally, hepatic arterial infusion chemotherapy (HAIC) can improve the prognosis of patients with advanced liver cancer. This real-world study aimed to evaluate the clinical efficacy and safety of HAIC combined with molecular targeted therapy and immunotherapy in the treatment of primary unresectable hepatocellular carcinoma (uHCC). A total of 135 patients with uHCC were enrolled in this study. Progression-free survival (PFS) was the primary endpoint. The efficacy of the combination therapy was assessed based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines. Overall survival (OS), adverse events (AEs) and surgical conversion rate were the secondary endpoints. Univariate and multivariate Cox regression analyses were performed to examine independent prognostic factors. For sensitivity analysis, inverse probability weighting (IPW) was used to balance the influence of the tested confounding factors between groups to verify the robustness of conversion surgery for survival benefits. The E-values were estimated to assess robustness to unmeasured confounders. The median number of therapies was three. Approximately 60% of the patients had portal vein tumour thrombosis (PVTT). The most common targeted drugs were lenvatinib and bevacizumab, whereas the most common immunotherapy drug was sintilimab. The overall objective response rate (ORR) was 54.1%, and the disease control rate (DCR) was 94.6%. A total of 97 (72%) patients experienced AEs of grades 3-4. Fatigue, pain and fever were the most common symptoms of grade 3-4 AEs. The median PFS was 28 months and 7 months in the successful and unsuccessful conversion groups, respectively. The median OS was 30 months and 15 months in the successful and unsuccessful conversion groups, respectively. Successful conversion surgery, sex, hapatic vein invasion, BCLC stage, baseline tumour size, AFP levels and maximum therapeutic response were independent prognostic factors for PFS. Successful conversion surgery, number of interventions, hapatic vein invasion and total bilirubin levels were independent prognostic factors for OS. After IPTW, no standardised differences exceeding 0.1 were found. IPW-adjusted Kaplan-Meier curves showed that successful conversion surgery was an independent prognostic factor for both PFS and OS. The E-values of successful conversion surgery were 7.57 and 6.53 for OS and PFS, respectively, which indicated a relatively robust impact of successful conversion surgery on the prognosis of patients. Patients with primary uHCC undergoing HAIC combined with immunotherapy and molecular targeted therapy have a higher tumour regression rate and the side effects are manageable. Patients undergoing surgery after combination therapy have survival benefits.

Abstract CT107: Phase Ib Study of Pembrolizumab in Combination with Intratumoral Injection of Clostridium novyi-NT in Patients with Advanced Solid Tumors

Abstract BACKGROUND: Intra-tumoral Clostridium novyi-NT (non-toxic) is an attenuated strain of C. novyi lacking alpha toxin replication within hypoxic tumor regions, causing tumor cell lysis and inflammation. Immunotherapy (IO) augments anticancer activity with intratumoral agents in prior preclinical and clinical studies. This phase 1b dose escalation study assessed safety and potential synergistic effects of pembrolizumab and C. novyi-NT in advanced solid tumors. METHODS: We enrolled patients with percutaneous injectable, solid tumors to receive single intratumoral injection of C. novyi-NT administered on Day 8 across 4 dose cohorts (3 × 10^4 to 100 × 10^4 spores, 3+3 design) with pembrolizumab 200mg IV Q3weekly starting on Day 0 up to 24 months. Primary objectives: Safety, tolerability and maximum tolerated dose (MTD) of combination. Secondary objectives: anti-tumor activity of combination in the injected tumor lesion and overall response by iRECIST 1.1. RESULTS: At data cutoff on October 24, 2022, 16 patients were enrolled and evaluable for toxicity and efficacy. It was well tolerated across all cohorts without dose limiting toxicities with median number of 5 cycles administered (1-34). 10 patients (63%) experienced progression; 1 withdrew consent; 1 completed therapy; 1 came off trial due to toxicity (immune related dermatitis) and 3 patients remain on trial. Median age was 62.5 years (40-71) while all patients (100%) had performance status of 1. 8 (50%) received prior IO and 7 (44%) had &amp;gt; 4 lines of prior therapies. Confirmed overall objective response rate (ORR) was 25% in 4 patients [non-keratinizing undifferentiated nasopharyngeal squamous carcinoma (NPC), human papilloma virus positive squamous cell carcinoma of base of tongue, vulvar melanoma and chordoma] with 3 partial responses (PR) and 1 complete response (CR). Among responders, median duration of response was 8.18 months and 1/4 (25%) had prior IO. NPC patient completed 24 months on trial to completion with best response at PR (-87%) while vulvar melanoma patient remains on trial with best response at CR (-100%). Median injected tumor size was 2.65cm (1-11) with confirmed ORR in injected lesions at 19% with 2 PRs and 1 CR. Most prevalent grade 1 and 2 adverse events were injection site reaction (25%), pyrexia (19%), pruritus (13%), leukopenia (13%) and anemia (13%). No grade 3 or 4 treatment related adverse events noted. Signs and symptoms of C. novyi-NT germination (infection) including fever, injection site pain, erythema, swelling, tenderness, and in some cases, ulceration, spontaneous drainage, tissue sloughing, bleeding, and malodor were observed in 5 patients. CONCLUSIONS: Intratumoral C. novyi-NT with pembrolizumab demonstrates clinical activity with favorable tolerability in patients regardless of tumor histology. This study is ongoing to define the recommended phase 2 dose (NCT03435952). Citation Format: Blessie Elizabeth Nelson, Filip Janku, Siqing Fu, Ecaterina I. Dumbrava, David S. Hong, Daniel Karp, Aung Naing, Jordi Rodon, Apostolia Tsimberidou, Rodabe N. Amaria, Anthony Conley, Senthil Damodaran, Kanwal P. Raghav, Brent L. Kreider, David Tung, Mary Varterasian, Khashayarsha Khazaie, Sarina Piha-Paul. Phase Ib Study of Pembrolizumab in Combination with Intratumoral Injection of Clostridium novyi-NT in Patients with Advanced Solid Tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT107.

Abstract CT152: A multicenter Phase II study of savolitinib in patients with MET-amplified gastroesophogeal junction adenocarcinomas or gastric cancer

Abstract Background: MET gene amplification is associated with poor prognosis in gastric cancer (GC) and gastroesophageal junction adenocarcinomas (GEJ). Savolitinib is a potent and highly selective oral MET tyrosine-kinase inhibitor. Here we reported the preliminary efficacy and safety from a phase 2 trial of savolitinib monotherapy in patients (pts) with MET-amplified advanced or metastatic GC/GEJ. (NCT04923932). Methods: Eligible pts had 2L+ GEJ or GC, with MET amplification and measurable lesions. Pts received savolitinib at 600 mg QD for body weight (BW) ≥50 kg, while 400 mg QD for BW &amp;lt;50 kg in 21-day cycles until disease progression or meeting other criteria for end of treatment. Savolitinib BID regimen has also been additionally explored. The primary endpoint was objective overall response rate (ORR) evaluated by Independent Review Committee (IRC). One interim analysis (IA) was pre-defined at the first 20 QD pts who had at least 2 tumor assessments. Results: As of IA, 20 pts were enrolled for QD regimen. Demographics and clinical outcomes are shown in table 1. The mean relative dose intensity of 93.07%. Median duration of exposure was 2.09 months. Confirmed ORR by IRC was 45%, and reached 50% in 16 patients with MET GCN (high) while only 1 PR was observed in 4 patients with MET GCN (low). Duration of response rate at 4-month was 85.7% with median follow up time of 5.5 months. The most common Gr≥3 TRAE (≥5%) were platelet count decreased, hypersensitivity, anemia, neutropenia and hepatic function abnormal. In all pts, only 1 patient discontinued treatment due to grade 4 liver function abnormal (TRAE) and no patient died due to TRAE. Conclusion: Savolitinib monotherapy had manageable safety and showed promising efficacy in pts with MET-amplified GEJ or GC, particularly in pts with MET high GCN. BID regimen is being investigated to further evaluate the efficacy and safety of savolitinib in pts with MET high GCN. Table 1. Pts baseline characteristics and clinical efficacy Baseline Characteristics ITT in IA (n=20) Median age (min, max), yearsSex (male/female), nECOG (0/1/2)Median BMI (min, max), (kg/m2)Primary location of tumor (GC/GEJ)Tumor stage (IV)Prior line of therapy (1/2/≥3)MET GCN (high/low) 57.00 (39.5, 76.8)17/33/15/220.8 (14.9, 25.8)16/4205/10/516/4 Clinical Efficacy By IRC By Investigator Confirmed objective response rateDisease control rate4m-DoR rate,% (95% CI) 45%65%85.7 (33.4, 97.9) 40%55%71.4 (25.8, 92.0) Citation Format: Zhi Peng, Hua Wang, Baorui Liu, Huiting Xu, Zhenyang Liu, Tianshu Liu, Jun Zhang, Yuxian Bai, Ying Yuan, Tao Wu, Feng Ye, Qinghua Pan, Jufeng Wang, Enxiao Li, Diansheng Zhong, Yueyin Pan, Yanru Qin, Yan Yang, Yusheng Wang, Aiping Zhou, Yongshun Chen, Dianbao Zhang, Hongli Liu, Xiujuan Qu, Shubin Wang, Ning Liu, Jinsheng Wu, Wei Li, Kejun Nan, Hongming Pan, Jianming Xu, Chunmei Bai, Heling Liu, Jia Wei, Runzhi Chen, Rongrong Li, Wei Li, Jinghong Zhou, Hongyan Yin, Qian Xu, Songhua Fan, Yongxin Ren, Weiguo Su, Lin Shen. A multicenter Phase II study of savolitinib in patients with MET-amplified gastroesophogeal junction adenocarcinomas or gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT152.

Potential predictive value of circulating tumor DNA (ctDNA) mutations for the efficacy of immune checkpoint inhibitors in advanced triple-negative breast cancer.

Background: In recent years, tumor immunotherapy has become a viable treatment option for triple negative breast cancer (TNBC). Among these, immune checkpoint inhibitors (ICIs) have demonstrated good efficacy in advanced TNBC patients with programmed death-ligand 1 (PD-L1) positive expression. However, only 63% of PD-L1-positive individuals showed any benefit from ICIs. Therefore, finding new predictive biomarkers will aid in identifying patients who are likely to benefit from ICIs. In this study, we used liquid biopsies and next-generation sequencing (NGS) to dynamically detect changes in circulating tumor DNA (ctDNA) in the blood of patients with advanced TNBC treated with ICIs and focused on its potential predictive value. Methods: From May 2018 to October 2020, patients with advanced TNBC treated with ICIs at Shandong Cancer Hospital were included prospectively. Patient blood samples were obtained at the pretreatment baseline, first response evaluation, and disease progression timepoints. Furthermore, 457 cancer-related genes were evaluated by NGS, and patients' ctDNA mutations, gene mutation rates, and other indicators were determined and coupled with clinical data for statistical analysis. Results: A total of 11 TNBC patients were included in this study. The overall objective response rate (ORR) was 27.3%, with a 6.1-month median progression-free survival (PFS) (95% confidence interval: 3.877-8.323months). Of the 11 baseline blood samples, 48 mutations were found, with the most common mutation types being frame shift indels, synonymous single-nucleotide variations (SNVs), frame indel missenses, splicing, and stop gains. Additionally, univariate Cox regression analysis revealed that advanced TNBC patients with one of 12 mutant genes (CYP2D6 deletion and GNAS, BCL2L1, H3F3C, LAG3, FGF23, CCND2, SESN1, SNHG16, MYC, HLA-E, and MCL1 gain) had a shorter PFS with ICI treatment (p < 0.05). To some extent, dynamic changes of ctDNA might indicate the efficacy of ICIs. Conclusion: Our data indicate that ICI efficacy in patients with advanced TNBC may be predicted by 12 mutant ctDNA genes. Additionally, dynamic alterations in peripheral blood ctDNA might be used to track the effectiveness of ICI therapy in those with advanced TNBC.

Efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer harboring BRAF mutations.

Despite immune checkpoint inhibitors (ICI) being widely used to treat patients with advanced non-small cell lung cancer (NSCLC), few studies examine the role of ICI in patients with proto-oncogene B-Raf, serine/threonine kinase (BRAF) mutations. A retrospective study was conducted for patients with BRAF-mutant NSCLC who received treatment at Shanghai Pulmonary Hospital between 2014 and 2022. Primary end point was progression-free survival (PFS). Secondary end point was best response (RECIST, version 1.1). The study involved a total of 34 patients with 54 treatments recorded. The median PFS for the whole cohort was 5.8 months and the overall objective response rate (ORR) was 24%. Patients who were treated with ICI combined with chemotherapy reported a median PFS of 12.6 months and an ORR of 44%. Those who were treated with non-ICI therapy came with a median PFS of 5.3 months and an ORR of 14%. Specifically, patients had better clinical benefits with first-line ICI-combined therapy. The PFS was 18.5 months whereas that of non-ICI group was 4.1 months. The ORR was 56% in ICI-combined group and 10% in non-ICI cohort. The findings observed an evidential and significant susceptibility to ICIs combined therapy in patients with BRAF-mutant NSCLC, especially in first-line treatment.