Positive Cancer Research Articles

Exploring Raloxifene-Based Metallodrugs: A Versatile Vector Combined with Platinum(II), Palladium(II) and Nickel(II) Dichlorides and Carborates against Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) poses challenges in therapy due to the absence of target expression such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Frequently, the treatment of TNBC involves the combination of several therapeutics. However, an enhanced therapeutic effect can be also achieved within a single molecule. The efficacy of raloxifene can be improved by designing a raloxifene-based hybrid drug bearing a 2,2'-bipyridine moiety (2). Integration of platinum(II), palladium(II), and nickel(II) complexes into this structure dramatically changed the cytotoxicity. The platinum(II) dichloride complex 3 did not demonstrate any activity, while palladium(II) and nickel(II) dichloride complexes 4 and 5 exhibited various cytotoxic behavior towards different types of hormone-receptor positive (HR+) cancer and TNBC cell lines. The replacement of the two chlorido ligands in 3-5 with a dicarbollide (carborate) ion [C2B9H11]2- resulted in reduced activity of compounds 6, 7, and 8. However, the palladacarborane complex 7 demonstrated higher selectivity towards TNBC. Furthermore, the mechanism of action was shifted from cytotoxic to explicitly cytostatic with detectable proliferation arrest and accelerated aging, characterized by senescence-associated phenotype of TNBC cells. This study provides valuable insights into the development of hybrid therapeutics against TNBC.

Fabrication of Metal Nuclear Acid Framework to Enable Carrier‐Free MNAzyme Self‐Delivery for Gastric Cancer Treatment

AbstractMulti‐component deoxyribozymes (MNAzymes) have shown extraordinary potential in precise gene therapy in vitro, however, the in vivo application is limited by complicated delivery systems. Herein, a novel DNA‐metal binding mechanism is discovered, and metal‐nucleic acid frameworks (MNFs) are built composed of MNAzymes and metal ions, which enable the carrier‐free self‐delivery of MNAzymes. Metal ions have a high affinity to DNA, however, the binding of metals with DNA at 20–30 base pair long (that normally a MNAzyme has) to form MNF structure is challenged by stringent high‐temperature synthesis conditions, poor stability of the products, and lack of targeting capabilities. While, it is discovered that through folding and entanglement of the MNAzyme with an aptamer tail, and prolonging the sequence to 71 base pair, the metal MNAzymes binding is significantly improved and stabilized to MNF structure even at room temperature. Moreover, the aptamer tail also endows MNFs with targeting capabilities. As proof of concept, a carrier‐free Ca/MNAzyme delivery system at room temperature, loaded with the model imaging protein BSA‐Cy5 is synthesized. This system can effectively target Her‐2 positive gastric cancer cells with the Her‐2 responsive aptamer tail and initiate dual gene regulation, thereby inducing energy depletion in cancer cells.

Kinome reprogramming as a therapeutic opportunity in ESR1 fusion driven breast cancer but not in gynecologic cancers.

1045 Background: The administration of specific tyrosine-kinase inhibitors in kinase fusion positive cancers has led to significant improvement in clinical outcomes. Gene fusions involving the ESR1 gene, a non-kinase, have been previously reported in breast and gynecologic cancers including ovarian cancer and uterine cancer. However, ERa inhibitors proved to be ineffective in ESR1 fusion positive cases, we have effectively characterized ESR1 fusions and hypothesized a surrogate downstream target as an effective approach to target ESR1 fusion positive breast cancer. Methods: We retrospectively analyzed 216,176 samples submitted for clinical molecular profiling at Caris Life Sciences via Caris MI Tumor Seek (Phoenix, AZ). Gene fusion detection was performed on mRNA isolated from a FFPE tumor sample using the Illumina NovaSeq platform. All ESR1 fusions with ≥ 3 junction reads were identified for manual review and for domain prediction, breakpoints, frame retention and co-occurring alterations by NGS. WES data was also investigated to evaluate co-occurring pathogenic mutations to establish the oncogenicity of gene fusions. Results: ESR1 fusions had the highest frequency in gynecologic and breast cancer. We evaluated ESR1 expression in cases with ESR1 fusions detected and observed higher expression of ESR1 in breast cancer, ovarian cancer (P<0.0001) and uterine cancer (P<0.0001) compared to respective cancer cases as determined by TPM values. The Kaplan-Meier curve also indicated poor prognosis for breast cancer patients with ESR1 fusions (619 days [n=105]) as opposed to patients who did not harbor any ESR1 variants (1396 days [n=755]; P<0.0001). Further, pathway analysis was performed on breast cancer ESR1 fusion positive and negative cases to discern specific downstream markers that might be upregulated. It was observed that RET(p<0.0001), IGF1R(p=0.0001) and FGFR3 (p<0.0001) were upregulated in ESR1 fusion positive breast cancer cases which may be largely determined by the TP53-FOXA1-ER alpha transcriptional axis. However, no significant increase of RET, IGF1R and FGFR3 was observed in gynecologic cancers, owing to high TP53 mutation frequency observed in ovarian cancer (90%) and uterine cancer (82%) compared to breast cancer(19%). Conclusions: We highlight that ESR1 fusions can be reliably detected in patients with breast cancer, ovarian cancer, and endometrial cancers. ESR1 fusions lose the ligand binding domain and cannot be targeted using current estrogen modulators or degraders. We have discovered the upregulation of oncogenic kinase signaling in ESR1 fusion positive breast cancer, but not in gynecologic cancers. Our observations highlight enhanced oncogenic kinase signaling as a surrogate approach with clinically approved kinase inhibitors for targeting ESR1 fusion positive breast cancer cases but not in ovarian and uterine cancers.

Evaluating disparities in receptor status, overall survival, and time to hormone therapy among women with breast cancer.

11096 Background: Breast cancer receptor status (ER/PR/HER2) is essential to guide treatment decisions. However, national race/ethnicity subtype studies rarely include Indigenous American Indian and Alaska Native (AI/AN) and Native Hawaiian and other Pacific Islander (NHPI) women. This study aims to compare across race/ethnicity: 1) hormone receptor (HR)/HER2 status, 2) Overall Survival (OS) for Triple Positive breast cancer, and 3) Time to Hormone Therapy (THT). Methods: A cohort study of women with breast cancer (Stage 1-4), age ≥18 years, diagnosed 2004-2017 was conducted with the National Cancer Database. Race was used as federally defined (White, Black, Asian, AI/AN, and NHPI) with Hispanic ethnicity. Primary endpoints were receptor status, OS, and THT (days from diagnosis to hormone therapy). Kaplan-Meier estimates and log-rank tests assessed OS. Multivariable logistic, Cox Proportional Hazard, and linear regression evaluated the likelihood of HR+/HER2+ (adjusted Odds Ratio [aOR]), death (adjusted Hazard Ratio [aHR]), and THT in days (adjusted β [aβ]), respectively, with 95% confidence intervals (95%CI). The majority non-Hispanic White population served as reference. All regressions were adjusted for sociodemographic and cancer characteristics. All HER2 analyses used a subset of women diagnosed post-2010, given inconsistent testing pre-2010. Results: 1,812,911 women were included who mostly had Stage 1 cancer (53%), from metropolitan areas (84%), with private insurance (51%), and a median age of 61 (IQR 51-71) years. Women were 81% White, 11% Black, 5% Hispanic, 2% Asian, 0.3% AI/AN, and 0.2% NHPI. NHPI women had the highest ER+ (84%) and PR+ (75%) cancers, while Asian women had the highest HER2+ (18%). Adjusted for covariates, only NHPI women were significantly more likely to have HR+ cancer (aOR=1.3, 95%CI=1.2-1.5) while Black women were less likely (aOR=0.6, 95%CI=0.6-0.6), compared to White women. Hispanic women were significantly more likely to have Triple Positive cancer (aOR=1.1, 95%CI=1.1-1.2) while Black women were less likely (aOR=0.9, 95%CI=0.9-0.9). Median follow-up was 63 (IQR 36-101) months. Among women with Triple Positive breast cancer, there were significant differences in OS (p< .0001) with 7-year survival ranging from 77% for NHPI women to 89% for Asian women. NHPI women had the highest risk of death (aHR=1.5, 95%CI=1.0-2.1), followed by AI/AN (aHR=1.5, 1.05-2.0), and Black (aHR=1.2, 95%CI=1.1-1.2). Adjusted for covariates, among women with HR+ breast cancer, longer THT occurred among Black (aβ=18 days, 95%CI=17-18), Hispanic (aβ=16 days, 95%CI=15-17), and NHPI women (aβ=14 days, 95%CI=9-18). Conclusions: NHPI women have higher HR+ rates while Black, Hispanic, and NHPI women with HR+ cancer experience longer times to hormone therapy. This is likely the first US analysis of breast cancer subtypes using federal race/ethnicity standards.

Real-world data of a regimen containing zimberelimab in the treatment of recurrent and metastatic cervical cancer.

e17521 Background: Cervical cancer is the malignant tumor in women. Zimberelimab is approved by NMPA for PD-L1 positive recurrent and metastatic cervical cancer. However, no real-world data of zimberelimab in recurrent and metastatic cervical cancer have been reported before. Methods: From August 2021 to March 2023, we retrospectively collected patient data at the First Affiliated Hospital of Nanchang University and Fujian Cancer Hospital. Patients with advanced or recurrent cervical cancer who had been pathologically diagnosed were eligible, regardless of whether they had squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma and PD-L1 status. All patients were treated with regimen containing zimberelimab. Date of brith, previous medical history, tumor stage at first diagnosis, metastatic sites, pathological type, HPV infection and PD-L1 expression status, and treatment regimen containing zimberelimab will be recorded. The primary endpoint was objective response rate and disease control rate assessed by RECIST1.1. The study has been approved by the First Affiliated Hospital of Nanchang University Ethics (No 317). (ChiCTR2300078205). Results: A total of 34 patients were eligible for evaluations of efficacy. 21 from the First Affiliated Hospital of Nanchang University and 13 from the Fujian Cancer Hospital. The median age was 53.23 years (range, 37–66). The ECOG PS was 1 for 23 cases (67.65%), 2 for 10 cases (29.41%).3 for 1 case (2.94%). Squamous cell carcinoma (28,82.35%) was the most common pathological subtype, and the most metastatic site were lymph node (26,76.47%), lung (10,29.41%), bone (6,17.65%), liver (1,2.94%), vulva (1,2.94%), peritoneal (1,2.94%) and bladder (1,2.94%). 32(94.12%) and 30(88.24%) patients have not test for PD-L1 statue or HPV infection. The best overall response of each patient was recorded to evaluate the efficacy. The objective response rate (ORR) in 34 patients were 52.94%, and the disease control rate (DCR) were 97.06%. And 25 patients had previously had ≥1 chemotherapy, and they was treated with a zimberelimab-based combination regimen. The ORR and DCR for these individuals were 52% and 96%, respectively. Conclusions: This is the first report of real-world data on zimberelimab, and zimberelimab combination therapy demonstrated quite good efficacy in patients with recurrence and metastatic cervical cancer who had previously received chemotherapy. Clinical trial information: ChiCTR2300078205. [Table: see text]

Patient characteristics, treatment patterns and early trends of lutetium Lu 177 vipivotide tetraxetan (177Lu-PSMA-617) use by US urologists and oncologists.

e17048 Background: 177Lu-PSMA-617 was approved by the US Food and Drug Administration in March 2022 for the treatment of patients with prostate-specific membrane antigen (PSMA) positive metastatic castration resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition (ARPI) and taxane-based chemotherapy. This study describes characteristics of patients treated with 177Lu-PSMA-617, treatment patterns and early trends in 177Lu-PSMA-617 utilization by US urologists (URO) and medical oncologists (ONC). Methods: This retrospective cohort study identified adult patients with ≥1 claim for 177Lu-PSMA-617 between 3/1/22 and 6/30/23 (first claim = index date) from the IQVIA open-source pharmacy and medical claims database. Patients were grouped by the physician specialty of the treating/referring physician. Patient characteristics were assessed within the 6 months prior to 177Lu-PSMA-617 initiation. Prior prostate cancer treatments were assessed over all available pre-index data. Results: Overall 1,394 patientstreated with 177Lu-PSMA-617 were identified during the first 16 months post-approval; 76.9% treated by an ONC and 23.1% treated by a URO. The mean age overall was 72.1 years; most patients were aged 65 and older (ONC, 83.3%; URO, 84.8%). Most patients had bone metastases (ONC, 88.0%; URO, 86.3%) and over one-third had visceral metastases (ONC, 34.6%; URO 35.7%). URO treated a higher proportion of patients with only lymph node metastases (5.9%) than oncologists (2.6%). Prior to 177Lu-PSMA-617, the vast majority of patients received ARPI and/or taxanes (ONC, 88.2%; URO, 89.4%). Use of 177Lu-PSMA-617 has steadily increased over the 16 months since approval with over five times as many patients being treated by ONC and URO in the first half of 2023. Conclusions: This is the first large-scale study describing 177Lu-PSMA-617 patient characteristics, prostatic cancer metastatic distribution, treatment patterns, and utilization trends by prescriber type (ONC and URO). This study highlights how URO are playing a pivotal role in management of post-taxane mCRPC patients receiving 177Lu-PSMA-617. As additional data with 177Lu-PSMA-617 becomes available, we anticipate the role of URO to significantly evolve with the potential for earlier use of 177Lu-PSMA-617 for pre-taxane mCRPC patients.

The role of stress in modulating AIPB expression and estradiol synthesis in triple-negative breast tumors.

e13146 Background: In the United States, invasive breast cancer affects 1 in 8 women during their lifetime, with over 3.8 million individuals living as survivors. Breast cancers vary, with some being hormone-responsive and categorized on the presence or absence of estrogen (ER), progesterone (PR), and HER2 receptors. While targeted therapies exist for Estrogen Receptor positive (Er+) and Progesterone Receptor positive (PR+) cancers, triple-negative breast cancer (TNBC), which lacks all three receptors, affects about 15% of patients and is unresponsive to effective molecular treatments. Only a fraction of the cases respond to chemotherapy which emphasizes a need for new prognostic markers and treatments. Aromatase is the key enzyme in converting testosterone to estradiol which plays a crucial role in tumor growth, especially after menopause. Our research lab has identified the “Aromatase Interacting Partner in Breast or AIPB, whose overexpression inhibits aromatase, leading to a reduction in estradiol levels. However, in triple-negative breast cancer, there is an increase in AIPB expression when compared to ER+/PR+/Her2- breast tumors or unaffected women. This devastating prognosis and low survival rates can contribute to a considerable amount of stress in the diagnosed patients, in turn leading to an increase in cortisol production. Our hypothesis suggests that this stress or increase in cortisol could alter AIPB production in the tumorigenic cells which could potentially lead to a decrease in estradiol synthesis. Methods: Stress stimulation was achieved in a lab setting by subjecting engineered triple-negative breast cancer cells, capable of conditional AIPB overexpression upon tetracycline addition, to a 42 °C heat shock for various durations (0,15, 30, 45 minutes). Results: Following the 45 minutes of stress, MDA-MMD-231 cells exhibited a significant reduction in estradiol levels, decreasing from 160ng/ml to 100ng/ml. MDA-MD-231 cells engineered to overexpress AIPB produced only 62ng/ml of estradiol, marking an 18.75% decrease. The introduction of doxycycline led to a further reduction in estradiol levels to 47ng/ml, which is approximately a 29.4% drop. Western blot analysis using a CT antibody revealed heightened AIPB expression in MDA-MD-231-AIPB cells when stress and doxycycline treatments were combined. Conclusions: Given the absence of aromatase in triple-negative breast cancer, our findings suggest that AIPB’s role in estradiol production is independent of aromatase, highlighting its significance in these cancer cells. The data supports the hypothesis that enhancing AIPB expression could potentially improve patient outcomes by reducing estradiol synthesis.

Exploration of different immunogenomic TMEs in gastric cancer based on HER2 and PD-L1 expression.

e16073 Background: Recent results from the KEYNOTE-811 study showed that first-line pembrolizumab was superior to placebo with respect to progression-free survival (PFS) in combination with trastuzumab and chemotherapy in patients with HER2 positive metastatic gastric cancer (GC). Interestingly, In the subgroup analysis, the PFS benefit with pembrolizumab was significant in patients with tumors with PD-L1 CPS ≥1, whereas there was no benefit in the small subgroup of patients with tumors with CPS < 1. Therefore, this study is to investigate immune-genomic differences in the tumor microenvironment according to the composition of surrounding cells and the expression status of HER2 and PD-L1. Methods: Utilizing single cell RNA sequencing (scRNA seq) and TCR sequencing, we examined 14 HER2 positive and 18 negative primary GC samples with CPS score based on PD-L1 IHC 22C3 pharmDx. Among the HER2-positive group, there were 4 samples in the CPS < 1 (negative) and 10 samples in the CPS ≥1 (positive) group. In the HER2 negative group, there were 6 samples in the CPS < 1 and 12 samples in the CPS ≥1. Results: First, when analyzing the distribution of total cells according to HER2 status, in the HER2 positive group, more endothelial cells ( p= 0.034) and fibroblasts ( p= 0.054) appeared in the PD-L1 negative group compared to the PD-L1 positive group, while there was no difference in the HER2 negative group. Furthermore, Through TCR analysis, the exhausted and cytotoxic score exhibit contrasting trends between HER2 negative and positive groups. In HER2-positive patients, the exhausted and cytotoxic score appear significantly higher in the CPS negative group. Next, we evaluated the proportion of immune cells according to HER2 status. The observed of CD4 Treg ( p= 0.084) and CD8 exhausted T (Tex), ( p= 0.036) cells was increased in the HER2 positive compared to the negative. When regrouped according to PD-L1 expression, only the HER2 positive group showed a tendency to increase the observation of CD4 Treg and CD8 Tex cells compared to positive in PD-L1 negative. In addition, we investigated whether the expression pattern of other immune checkpoint molecules differed depending on the PD-L1 expression pattern in both HER2 positive and negative patients. In the HER2 negative group, the expression of immune checkpoint proteins was similar regardless of the CPS expression group, or the expression of some proteins was higher in the CPS positive group. In other hands, in HER2 positive, CPS < 1 group had higher expression of immune checkpoint proteins, such as PDCD1, LAG2, BTLA, VISTA and TIGHT. Conclusions: The high proportion of CD4 Tregs, CD8 Tex and the elevated exhausted score in the subgroup with CPS < 1 in HER2 positive GCs suggesting immune exclusive environment compared to her-2 and PD-L1 coexpressing group. Considering increased expression of immune checkpoint proteins other than PD-1/PD-L1, for patients with HER2-positive and CPS < 1, combination therapy with other immune checkpoint inhibitors rather than anti-PD-1/PD-L1 may be suggested.

AMPLIFY-7P, a first-in-human safety and efficacy trial of adjuvant mKRAS-specific lymph node targeted amphiphile ELI-002 7P vaccine in patients with minimal residual disease–positive pancreatic and colorectal cancer.

AMPLIFY-7P, a first-in-human safety and efficacy trial of adjuvant mKRAS-specific lymph node targeted amphiphile ELI-002 7P vaccine in patients with minimal residual disease–positive pancreatic and colorectal cancer.

GOG3069: Phase 2 study of alpelisib and fulvestrant for PIK3CA-mutated estrogen receptor (ER)-positive endometrioid endometrial cancers.

TPS5639 Background: Treatment options for persistent, metastatic, or recurrent endometrial cancer continues to evolve as we learn more about the molecular landscape of this disease. Recent studies have shown a benefit to endocrine-based combinations such as aromatase inhibitors with mTOR or CDK4/6 inhibitors especially in patients who had not received prior chemotherapy ( 1– 3). The presence of oncogenic PIK3CA mutations have been shown to impact response to aromatase inhibitors in breast cancer. The combination of alpelisib and fulvestrant was approved for the treatment of metastatic hormone receptor-positive, HER2-negative breast cancer harboring oncogenic mutations in the PIK3CA gene that progressed on prior endocrine therapy( 4). PIK3CA mutations are commonly identified in endometrial cancers and may similarly confer endocrine resistance. GOG3069 is a phase II trial designed to evaluate the efficacy and safety of alpelisib and fulvestrant in a biomarker-selected endometrial cancer patient population. Methods: This is a phase II non-randomized, open label, multicenter, two-stage study. Eligible patients must have advanced (FIGO 2014 Stage III or IV), persistent, or recurrent endometrial carcinoma with measurable disease by RECISTv1.1 criteria. Patients cannot be curable by surgery or radiotherapy. Disease must be of endometrioid histology with positive expression of estrogen receptor (defined as ≥1% of tumor cells demonstrating positive nuclear staining by immunohistochemistry) and oncogenic PIK3CA mutation. Patients may have received no more than 3 prior lines of therapy including 1 prior line of systemic chemotherapy. Enrolled patients will receive treatment with alpelisib 300mg orally daily and fulvestrant 500mg IM on Day 1 and Day 15 of Cycle 1, then 500mg IM on Day 1 of each 28-day cycle. The primary endpoint is overall response rate as measured by RECISTv1.1-defined tumor response. Secondary endpoints include safety, tolerability, progression-free survival, duration of response, and 24-month overall survival rate. GOG3069 activated in November 2023 and expects to enroll across 15 US sites. The statistical plan uses a conditional stratified design factoring differing probabilities of response based on whether the patient had prior chemotherapy exposure. ClinicalTrials.gov Identifier: NCT05154487

Characterization of long-term survivors from four clinical trials examining patients with folate receptor alpha–positive recurrent ovarian cancer treated with single-agent mirvetuximab soravtansine.

Characterization of long-term survivors from four clinical trials examining patients with folate receptor alpha–positive recurrent ovarian cancer treated with single-agent mirvetuximab soravtansine.

A phase II study of fulvestrant and abemaciclib in hormone receptor positive advanced or recurrent endometrial cancer.

A phase II study of fulvestrant and abemaciclib in hormone receptor positive advanced or recurrent endometrial cancer.

Efficacy and safety of SY-5007, a highly potent and selective RET inhibitor, in Chinese patients with advanced RET-fusion positive non-small cell lung cancer (NSCLC): Results from a multicenter, single-arm, phase II study.

Efficacy and safety of SY-5007, a highly potent and selective RET inhibitor, in Chinese patients with advanced<i> RET</i>-fusion positive non-small cell lung cancer (NSCLC): Results from a multicenter, single-arm, phase II study.

A multicenter, prospective phase II trial of first-line osimertinib treatment for patients with poor performance status and EGFR mutation–positive non-small cell lung cancer (OPEN/TORG2040).

A multicenter, prospective phase II trial of first-line osimertinib treatment for patients with poor performance status and <i>EGFR</i> mutation–positive non-small cell lung cancer (OPEN/TORG2040).

Are we ready to use PSMA as a theranostic biomarker in clinical practice for patients with breast cancer?

e13114 Background: Subtype classification for breast cancer (BC) patients is important for risk-stratification. Unfortunately, this parameter is not able to discriminate perfectly between high- and low-risk disease and the identification of an accurate biomarker to determine aggressiveness is still a clinical need. Prostate-specific membrane antigen (PSMA) could be important given that it has been reported to be expressed in BC tumor cells and even more in endothelial cells of tumor vessels. Methods: We analyzed 101 BCs of whom 22 luminal A, 34 Luminal B, 22 HER2 positive and 23 triple negative (TN) BC to assess whether PSMA expression by immunohistochemistry was different in tumor subtypes and was related to ki67 expression and stromal (tumour-infiltrating lymphocytes) TILs. PSMA positivity was calculated as the number of positive vessels on 10 fields at 40X magnifications. Kruskal Wallis’s test was used to assess difference in PSMA positivity among BC subgroups and Dunn’s test was performed for post-hoc comparisons; Spearman’s rho coefficient was calculated to analyze the correlation among PSMA, KI67 and TILs. Results: The median age at diagnosis of BC patients was 66 (min-max: 25-87 years). Seventy (69.3%) patients had ER&gt;0 and 64 (63.4%) had PgR&gt;0. The ductal histotype was present in 92 patients (91%). The majority of the patients had grade 3 tumors (55.4%). Considering the number of positive vessels, our results showed that median PSMA was higher in TNBC compared to Luminal A, Luminal B and HER2 positive tumors (p&lt;0.001, p=0.001 and p=0.041, respectively). Ki67 was higher in TNBC compared to Luminal A, Luminal B and HER2 positive tumors (p&lt;0.001, p&lt;0.001 and p=0.001, respectively). We saw a correlation between PSMA and ki67, especially in HER2 positive tumors (p&lt;0.001), while a correlation between PSMA and TILs was observed in Luminal A (p=0.028). The analysis of PSMA expression on the lymph nodes showed the same trend observed for the primary tumors given that it was higher in TNBC compared to HER2 positive and luminal cancers. Conclusions: Our results suggest that PSMA could be used as a theranostic biomarker in BC considering that it is highly expressed in more aggressive tumors and the possibility to treat PSMA expressing patients for anti-angiogenesis and/or radionuclide treatment.

A phase 2, multicenter, open-label, dose-optimization study evaluating telomere-targeting agent THIO sequenced with cemiplimab in patients with advanced NSCLC: Updated results.

8601 Background: Despite recent approvals for the first-line (1L) treatment of advanced non-small-cell lung cancer (NSCLC), long-term prognosis remains poor with a 5-year survival rate of 28% and limited options exist in patients (pts) refractory or resistant to immune checkpoint inhibitors (ICI). THIO (6-thio-2’-deoxyguanosine) is a small molecule, first-in-class direct cancer telomere-targeting agent that selectively targets telomerase positive (TERT+) cancer cells. It is incorporated de novo in synthesized telomeres leading to chromatin uncapping, generation of DNA damage signals, and rapid apoptosis. In advanced cancer animal models, THIO followed by an ICI demonstrated the ability to overcome ICI resistance. Methods: Here we describe a phase 2 dose-optimization study (NCT05208944) for adults with advanced NSCLC who progressed or relapsed after 1–4 prior treatment (tx) lines including 1L ICI alone or in combination with platinum chemotherapy. Following a safety lead-in of 10 pts who received THIO 360 mg IV [120 mg QD, D1–3] followed by 350 mg IV cemiplimab on D5 Q3W, the study proceeded to a 2-stage design with pts randomized to 1 of 3 arms: THIO 60 mg, 180 mg, or 360 mg, all followed by cemiplimab Q3W. In Stage 1 if at least 8 of 19 pts/arm achieved disease control, an additional 22 pts could be enrolled in that arm (up to 41 pts/arm). Study endpoints include safety (DLTs and AEs/SAEs) and efficacy (ORR, DCR, DOR, PFS, and OS). Results: Recruitment into the 360 mg arm was paused after 4 pts following 1 instance of G4 ALT Increase and AST Increase (without clinical presentation). At the end of Stage 1 cut-off (13-Nov-2023), the DCR greatly exceeded the threshold required for Stage 2 expansion in both arms: 60 mg 14/16 (88%); 180 mg 11/13 (85%). The 180 mg dose was selected for further investigation by the trial’s Safety Review Committee based on superior efficacy (31% PR rate; 54% reduction in tumor burden). As of 8-Jan-2024, 56 pts received ≥1 dose of THIO in the 60 and 180 mg arms (24 and 32 pts, respectively). Prior lines of tx at study entry were: 60 mg (1L 75%, 2L 21%, 3L 4%); 180 mg (1L 66%, 2L 31%, 4L 3%). Most pts received platinum chemotherapy prior to study entry (60 mg 88%; 180 mg 78%). Across all pts treated n=70, most AEs were G1/2. The most frequent related AEs were AST increase (23%), ALT increase (20%), and nausea (11%). All instances of LFT elevations were without clinical symptoms and resolved to baseline. Conclusions: THIOfollowed by cemiplimab was generally well tolerated in this difficult-to-treat population (all pts progressing following ICI tx and the majority following platinum chemotherapy). Based on safety and promising efficacy, the 180 mg dose was selected for further development. Enrollment is ongoing and is expected to be completed in Feb-2024. Updated primary endpoint data, including preliminary durability data, will be presented. Clinical trial information: NCT05208944 .

Focus on human epidermal growth factor receptor 2 (HER2) positive metastatic colorectal cancer (HER2+ mCRC): A real world retrospective analysis.

3080 Background: HER2+ mCRCs, displaying HER2 overexpression or ERBB2 amplification, represent a rare molecular subset, accounting for 2- 6% of all mCRCs. HER2+ mCRCs are thought to be enriched in KRASwt pts and associated with distal primary tumor location. While its prognostic value is debated, HER2 seems a negative predictor for antiEGFR agents. Recently, its role as a potential actionable target has emerged, with promising results in refractory mCRC. Despite that, nowadays HER2 testing is not routinely included in the diagnostic workup of mCRC. Methods: This is an observational, retrospective, multicenter study, aiming to investigate and describe clinical and molecular features and prognostic value of HER2+ mCRCs from real world pts. Pts with mCRC tested for HER2 status who received at least one line of therapy (tx) at 11 Italian Institutions within the Lazio Region between Mar2011 and Jan2024 were enrolled. HER2 status was assessed either for HER2 overexpression using IHC according to the HERACLES diagnostic criteria or for ERBB2 amplification using NGS, followed by IHC confirmation for positive cases. Differences between groups for categorical variables were compared using the Chi Square test. Endpoint for prognostic assessment was OS, estimated with the Kaplan-Meier method and compared using log-rank test. Endpoints for predictive assessment were RR and DCR. Statistical significance was set at p .05. Results: 422 pts were included, of those 38 pts had a HER2+ mCRC (9%). HER2 positivity was more frequent among patients with RASwt tumor compared to RASmt (12.2 vs 6.1%; p .029), lung metastasis ( p .013) and synchronous metastatic disease ( p .044). No correlation with age, sex, primary tumor location, peritoneal spread, histologic grading and mucinous histology was observed. At a median FU of 19 months, OS was significantly shorter in HER2+ compared to HER2- mCRCs (HR 2.17, 95%CI 1.14-4.13; p .017). 104 pts with RASwt mCRC received an antiEGFR-based first line tx and were evaluable for response; of those 96 were HER2- and 12 HER2+. RR was higher for HER2- tumors (80 vs 42%; p .003), while no difference was observed for DCR (96 vs 83%; p .085). Of 38 HER2+ tumors, 14 received an antiHER2 tx, of those 11 were RASwt and 3 RASmt. RAS status did not impact on antiHER2 activity (DCR 64 vs 33% for RASwt and RASmt; p .347). Conclusions: We showed that HER2+ mCRCs are more frequently, although not exclusively, RASwt, display a lung tropism, present with synchronous metastases and have a negative prognosis. Moreover, in accordance with results from DESTINY-CRC02, the target actionability seems to be retained irrespective of RAS status. Given also the possible use in first line of antiHER2 tx in the near future, the baseline molecular diagnostic workup of mCRC must include HER2 status assessment, irrespective of RAS mutational status and primary tumor location.

A phase II, open-label, single-arm, multicenter, efficacy and safety study of 80 mg osimertinib in patients with leptomeningeal metastases (LM) associated with epidermal growth factor receptor (EGFR) mutation–positive non-small cell lung cancer (NSCLC): BLOSSOM.

A phase II, open-label, single-arm, multicenter, efficacy and safety study of 80 mg osimertinib in patients with leptomeningeal metastases (LM) associated with epidermal growth factor receptor (EGFR) mutation–positive non-small cell lung cancer (NSCLC): BLOSSOM.

Efficacy and safety of LM-108, an anti-CCR8 monoclonal antibody, in combination with an anti-PD-1 antibody in patients with gastric cancer: Results from phase 1/2 studies.

2504 Background: Targeting tumor-infiltrating regulatory T cells (Tregs) is a potential approach to overcome immunotherapy resistance in the treatment of cancers. LM-108 is a novel Fc-optimized, anti-CCR8 monoclonal antibody that selectively depletes tumor-infiltrating Tregs. Here we report a pooled analysis of results from 3 phase 1/2 studies (NCT05199753; NCT05255484; NCT05518045) to evaluate the efficacy and safety of LM-108 in combination with anti-PD-1 therapy in patients with gastric cancer. Methods: Eligible patients with gastric cancer treated with LM-108 in combination with an anti-PD-1 antibody were included in the analysis. Patients received intravenous LM-108 at dose levels of 3 mg/kg Q2W, 6 mg/kg Q3W, or 10 mg/kg Q3W plus an anti-PD-1 antibody (intravenous pembrolizumab 200 mg Q3W or 400 mg Q6W or toripalimab 240 mg Q3W). The primary endpoint was investigator-assessed ORR per RECIST v1.1. The secondary endpoints included safety, other efficacy outcomes, and biomarkers analysis. Data cutoff date for the pooled analysis was December 25, 2023. Results: Forty-eight patients with gastric cancer (median age: 60.5 years; male: 72.9%) from China, USA, and Australia were treated ≥ 1 dose of LM-108 in combination with pembrolizumab or toripalimab. Most (n = 47, 97.9%) patients had received at least 1 prior anticancer treatment, and 43 (89.6%) had received prior anti-PD-1 therapy. Treatment-related adverse events (TRAEs) occurred in 39 (81.3%) patients, in which the most common events (≥15%) were alanine transaminase increased (25.0%), aspartate transaminase increased (22.9%), white blood cell decreased (22.9%), anemia (16.7%). Grade ≥ 3 TRAEs occurred in 18 (37.5%) patients, the most common events (≥ 4%) were anemia (8.3%), lipase increased (4.2%), rash (4.2%), and lymphocyte count decreased (4.2%). Among 36 efficacy-evaluable patients across all regimens, ORR was 36.1% (95% CI 20.8%–53.8%) and DCR was 72.2% (95% CI 54.8%–85.8%). The median PFS was 6.53 months (95% CI 2.96–NA). Among 11 patients whose disease had progressed on first-line treatment, ORR was 63.6% (95% CI 30.8%–89.1%) and DCR was 81.8% (95% CI 48.2%–97.7%). Of the 11 patients who progressed on first-line treatment, 8 had high CCR8 expression. Among these 8 patients, ORR was 87.5% and DCR was 100%, with 1 CR, 6 PR, and 1 SD observed. Conclusions: LM-108 in combination with an anti-PD-1 antibody showed promising antitumor activity in patients with gastric cancer that was resistance to anti-PD-1 therapy. The combination therapy was well tolerated. These results support further evaluation of LM-108 in CCR8 positive gastric cancer. Clinical trial information: NCT05199753 ; NCT05255484 ; NCT05518045 .

Single-cell sequencing to elucidate the disparities in the immune microenvironment between PIK3CA mutants and wild types.

e17524 Background: In patients with cervical cancer, PIK3CA exhibits the highest mutation rate, with the predominant oncogenic alteration reported to occur in 40% of cases. Recent studies in cervical cancer have indicated that the mutation status of PIK3CA is prominently associated with a diminished overall survival. Nevertheless, in our preceding study entitled 'Efficacy and Safety of Sintilimab Plus Anlotinib for PD-L1–Positive Recurrent or Metastatic Cervical Cancer: A Multicenter, Single-Arm, Prospective Phase II Trial', the prognosis for the mutant group surpassed that of the non-mutant group. Therefore, distinguishing the differences in the immune microenvironment between PIK3CA mutant and wild-type cervical cancer patients is of great significance. Methods: We used Single-cell RNA sequencing (scRNA-seq) to analyze the tissue samples of 7 cervical cancer patients with PIK3CA mutations and 9 with wild-type. Results: We partitioned cells from both the mutated and wild-type forms of cervical cancer into nine distinct clusters. To better understand the transcriptional heterogeneity of tumor-infiltrating T lymphocytes, we re-clustered 45,574 NK/T cells into 9 clusters. A specific cell cluster, designated as CD8+ ISG15, exhibited a significant enrichment in interferon-induced genes, including ISG15, IFIT3, IFIT1, RSAD2, and IFI6. To explore intergroup differences, we performed differential analysis on the proportions of mutations and non-mutations in different subgroups. We found significant differences in CD8+ ISG15 between the mutant group and the widegroup. ISG15 plays a pivotal role in antiviral responses, and as research advances, it has been identified as a potential prognostic biomarker and therapeutic target for cancer, beyond its antiviral function. A growing body of studies indicates that ISG15 is overexpressed in the majority of tumors, however, the influence of high ISG15 expression on the overall survival of cancer patients is dependent on the cancer type. In our single-cell analysis of cervical cancer, we observed that the CD8+ ISG15 subgroup specifically expresses ISG15, and the prevalence of this subgroup is significantly greater in the PIK3CA wild-type group compared to the mutant group. Consequently, the CD8+ ISG15 subgroup is perceived as a significant subset within the cervical cancer immune microenvironment for regulating anti-tumor responses. Conclusions: We defined the CD8+ ISG15 cell cluster present in the cervical cancer immune microenvironment using scRNA-seq, and found that its proportion is significantly lower in the PIK3CA mutant group than in the wild-type group. Combined with existing research, this suggests that this subgroup plays an important role in immune regulation within the cervical cancer immune microenvironment.