INTRODUCTION:It is estimated that 10-25% of breast cancer patients have metastatic disease upon diagnosis with roughly 20% having limited metastatic sites. The optimal management of patients with de novo bone-only oligometastatic breast cancer (OMBC), particularly curative-intent approaches, continues to evolve given extremely limited evidence in survival outcomes with this strategy. METHODS:This was a single-center retrospective review of the survival outcomes and details of treatment of patients with de novo OMBC who received tri-modality treatment with systemic therapy (chemotherapy with or without endocrine treatment and/or HER2-directed therapy), surgery, and radiotherapy to local and metastatic site/s. Progression-free survival (PFS) was defined as the time from initiation of treatment (either surgery, or neoadjuvant systemic therapy) to date of clinical or radiologic progression. RESULTS:From January 2014-March 2024, we identified 10 women who fit the inclusion criteria. Seven had isolated bone metastasis, and none had more than 3 metastatic sites. The included cohort had a mean age of 44.2 years. Nine had hormone receptor-positive disease, and 5 were HER2-positive. All patients were discussed in a multidisciplinary meeting. Median PFS by Kaplan-Meier analysis was 40.2 months. Nine patients were still alive at the time of analysis, and 6 of them remain disease free with a median follow-up duration of 30.8 months. CONCLUSION:Our cohort of women with de novo bone-only oligometastatic breast cancer who underwent standard curative-intent tri-modality approach and ablative radiation to metastatic sites had a long median PFS and was rendered disease-free for many years using this approach.

Abstract Background: Access to early-phase clinical trials (EPCTs) remains limited increasing despite genomic testing, suggesting that operational barriers rather than biomarker detection constrain enrolment. Tissue next generation testing to guide EPCT enrolment introduces delays which can hamper eligibility in a rapidly evolving EPCT landscape with increased slot competition and trial complexity. PANNA-COTA evaluated whether EPCT access can be improved by integrating circulating tumour DNA (ctDNA) profiling within real-time, network-level trial navigation across a state-wide EPCT consortium improves trial access. Methods: PANNA-COTA was a prospective, multicentre study across nine sites within the NSW Early Phase Clinical Trials Alliance (NECTA) Australia. Patients with advanced solid tumours referred for EPCT consideration underwent ctDNA testing (Guardant360®) followed by centralised molecular tumour board (MTB) review incorporating cross-site trial mapping and real-time slot availability. The primary endpoint was EPCT enrolment at 3 months. Secondary endpoints included overall enrolment, impact of ctDNA on recommendations, and clinical outcomes. Results: Of 104 consented patients, 101 were evaluable. Median age was 63 years; 61% had ≥3 prior lines of therapy and 48% had no prior tumour NGS. ctDNA alterations were detected in 85%, with actionable alterations in 44%. Therapeutic options were identified in 88% and EPCTs recommended in 76% of patients. ctDNA influenced MTB recommendations in 51% of cases. EPCT enrolment was 37% (37/101) at 3 months and 47% (47/101) overall (median follow-up 16.3 months). Despite this, only 7% received genomically matched therapy. Among trial participants, disease control rate was 81% and objective response rate was 33%, with 70% enrolled onto antibody drug conjugate (ADC) trials. After MDT discussion, oncologist confidence in EPCT selection based upon Likert scale ratings pre-post ctDNA result and MDT discussion increased in 47/85 (55%) of cases. Conclusions: PANNA-COTA demonstrates that integrating rapid ctDNA profiling within a network-based, real-time trial navigation system enables high EPCT enrolment despite low rates of genomically matched therapy. These findings highlight a critical disconnect between genomic actionability and trial access. EPCT navigation, eligibility, and system-level coordination were identified as the dominant determinants of enrolment. This model supports a shift from passive molecular testing toward active, network-enabled trial allocation in precision oncology drug development and delivery. Citation Format: Jia Liu, Max Farrow, Sandra Hsing, Rasha Cosman, Charlotte Rose. Lemech, Christina Teng, Abhijit Pal, Udit Nindra, Andrew Parsonson, John JW. Park, Anthony Rodrigues, Wei Chan, Joe Wei, Jordan Cohen, Craig Underhill, Daniel Brungs, Mun Hui, Adnan Nagrial, Suyog Jain, Anthony M. Joshua. Network-integrated clinical trial navigation with ctDNA profiling improves early-phase trial access: Final results from the PANNA-COTA study [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr A056.

Background: Histone lysine acetyltransferase KAT6A, and its paralog, KAT6B regulate lineage specific gene transcription via H3K23 acetylation. PF-07248144 is a novel selective catalytic inhibitor of KAT6 (6A & 6B). We report updated results (with 7 months additional follow-up) of clinical safety, efficacy, and additional subgroup analyses from the phase 1 study (NCT04606446) of PF-07248144 as monotherapy and with fulvestrant (fulv) in heavily pretreated ER+HER2− metastatic breast cancer (mBC). Methods: Patients (pts) had metastatic ER+ HER2− mBC and had progressed after a CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET). Pts received PF-07248144 at the recommended expansion dose (RDE) of 5 mg QD as monotherapy or with fulv. Primary objective: safety and tolerability per CTCAE 5.0. Secondary objectives: antitumor activity per RECIST 1.1 and pharmacokinetics. Exploratory objectives: Pharmacodynamics and predictive biomarkers. Circulating tumor DNA (ctDNA) and gene mutations were evaluated by Guardant 360 assay. Results: 35 pts received PF-07248144 monotherapy and 43 pts with fulv. All 78 pts had received prior CDK4/6i and ET in the metastatic setting. 59% (46/78) had detectable ESR1 mutations at baseline. PF-07248144 demonstrated tolerable safety profile at RDE and encouraging antitumor activity as monotherapy and with fulv. In all 78 pts, the most frequent treatment-related adverse event (TRAE) was grade (G) 1/2 dysgeusia (n=66, 84.6%), mainly G1 (n=50, 64.1%); no dose reduction and treatment discontinuation due to dysgeusia. The most frequent G≥3 TRAE was neutropenia (G3: n=29, 37.2%; G4: n=5, 6.4%), reversible and manageable with dose modification. No febrile neutropenia or G5 TRAEs. As of 30 Apr 2024, we observed increased antitumor activity with longer follow-up (median 16.4 mos) for fulv combination (n=43). The objective response rate (ORR) was 37.2% (95% CI 23.0, 53.3), median duration of response was not reached (95% CI 7.2 mos, not evaluable), clinical benefit rate was 55.8% (95% CI 39.9, 70.9), and the median progression-free survival (mPFS) was 10.7 mos (95% CI 5.3, 13.8). Antitumor activity was observed irrespective of ESR1 (wild-type [WT] n=18, mutant [MT] n=24; ORR 33.3 vs 41.7%; mPFS 10.9 vs 10.7 mos) and PIK3CA/AKT1/PTEN (WT n=23, MT n=19; ORR 43.5 vs 31.6%; mPFS 13.7 vs 7.3 mos) mutation status. Additional subgroup analyses revealed broad antitumor activity of PF-07248144 fulv combination in pts treated as second-line (2L) therapy (following 1L CDK4/6i + ET) or as third-line or beyond (3L+) therapy (ET, targeted therapy or chemotherapy in between; ORR 30.4% [7/23] vs 45.0% [9/20]; mPFS 13.8 vs 10.7 mos); and irrespective of primary or secondary endocrine resistance (ORR 57.1% [4/7] vs 33.3% [12/36]; mPFS 9.0 vs 10.8 mos), presence or absence of prior treatment with fulv (ORR 60.0% [3/5] vs 34.2% [13/38]; mPFS not reported [n≤5] vs 7.5 mos), and rapid progression on prior CDK4/6i (duration of treatment <6 mos) or prior CDK4/6i treatment duration >12 mos (ORR 50.0% [2/4] vs 36.4% [12/33]; mPFS not reported [n≤5] vs 10.9 mos). After 8-wk treatment, the median reduction in total ctDNA and ESR1 mutant allele frequency was 95.0% and 100.0%. Pts with non-detectable ctDNA after the initial 8-wk treatment had longer PFS compared with those with detectable ctDNA. Conclusions: PF-07248144 in combination with fulv demonstrated an acceptable safety profile and promising efficacy in pts with ER+ HER2− mBC post CDK4/6i and ET. Antitumor activity was observed irrespective of ESR1 and PIK3CA/AKT1/PTEN mutation status, endocrine sensitivity or resistance, duration of prior CDK4/6i treatment (<6 mos or >12 mos), prior fulvestrant treatment, and 2L or later line therapy. These findings suggest that PF-07248144 in combination with ET may potentially overcome endocrine resistance and CDK4/6i resistance and provide a novel mechanism to address high unmet medical need in HR+ mBC after prior CDK4/6i and ET. Citation Format: Toru Mukohara, Patricia M. LoRusso, David Sommerhalder, Kan Yonemori, Erika Hamilton, Sung-Bae Kim, Seock-Ah Im, Geoffrey J. Lindeman, Hope S. Rugo, Hiroji Iwata, Rachel M. Layman, Gun Min Kim, Toshinari Yamashita, Jee Hyun Kim, Fengting Yan, Toshio Shimizu, Yee Soo Chae, Timothy Clay, Rohit Joshi, Monica Mita, Mun Hui, Brian Dong, Brooke Holbrook, Sean Kent, Athanasia Skoura, Li Liu, Meng Li, Yeon Hee Park. PF-07248144, a first-in-class KAT6 inhibitor, in patients with HR+ HER2− metastatic breast cancer: Updated results from phase 1 dose expansion study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-04-28.

PURPOSE:GFH018 is a novel TGF-β type I receptor inhibitor, which has been shown to potentiate the antitumor effect of anti-PD-1/PD-L1 blockade. This study aimed to evaluate the safety and efficacy of GFH018 plus toripalimab in patients with recurrent/metastatic (R/M) nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS:This phase Ib/II study included patients with specific solid tumors who had failed at least one prior line of standard therapy. Patients received GFH018 (40 or 80 mg) twice a day for 14 days on/14 days off, combined with toripalimab (3 mg/kg) intravenously every 2 weeks on a 28-day cycle. Treatment continued until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), duration of response (DoR), and safety. RESULTS:Forty-six patients with R/M NPC were accrued. The ORR was 26.1% [90% confidence interval (CI), 15.8%-38.8%], and the disease control rate (DCR) was 43.5% (90% CI, 31.0%-56.6%). The median PFS was 2.0 months (90% CI, 1.8-8.9), and the median DoR was 7.6 months (90% CI, 5.6-not reached). In patients without prior immune checkpoint inhibitor (ICI) treatment, the ORR was 40% (90% CI, 23.6%-58.3%) and the DCR was 60% (90% CI, 41.7%-76.4%). The median PFS was 9.0 months (90% CI, 1.9-not reached), and the median DoR was not reached. In patients previously exposed to ICIs, the ORR was 9.5% (90% CI, 1.7%-27.1%) and the DCR was 23.8% (90% CI, 9.9%-43.7%). High parenchymal CD8+ T-cell density correlated with better PFS in these patients. Data from other solid tumor cohorts will be reported in future analyses. CONCLUSIONS:The combination of GFH018 and toripalimab showed a manageable toxicity profile and durable antitumor activity in patients with R/M NPC, especially those without prior ICI exposure.

Objective To evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary antitumour activity of AMG 404, a fully human IgG1 monoclonal antibody targeting programmed cell death-1, in patients with advanced solid tumours.Design First-in-human phase I study comprising eight dose expansion cohorts, including cohorts with microsatellite instability-high (MSI-H) tumours and non-small cell lung cancer with high programmed death-ligand 1 expression (NSCLC/PDL1-H, tumour proportion score ≥50%).Setting Conducted across 28 global sites.Participants This study enrolled adult patients with histologically or cytologically confirmed metastatic or locally advanced solid tumours not amenable to curative treatment with surgery or radiation. The inclusion criteria included a life expectancy of >3 months, ≥1 measurable or evaluable lesion per modified Response Evaluation Criteria in Solid Tumours (RECIST) V.1.1, an Eastern Cooperative Oncology Group performance status of ≤2 and adequate haematological, renal and hepatic function. Patients with prior treatment with checkpoint inhibitors, primary brain tumour or untreated or symptomatic brain metastases and leptomeningeal disease and history of other malignancy within the past 2 years were excluded.Interventions The planned doses were 240 mg, 480 mg and 1050 mg of AMG 404 administered every 4 weeks (Q4W).Primary and secondary outcome measures Primary endpoints were dose-limiting toxicities (DLTs), treatment-emergent adverse events, treatment-related adverse events, changes in vital signs and clinical laboratory tests. Secondary endpoints included PK parameters, incidence of antidrug (AMG 404) antibodies and antitumour activity assessed per modified RECIST V.1.1 (objective response, duration of response, progression-free survival (PFS), disease control and duration of stable disease).Results A total of 171 patients were enrolled; 168 were treated. Median (range) follow-up was 36.3 weeks (1.6–137.1). No DLTs were observed. Grade 3 and serious treatment-related adverse events occurred in 16 (9.5%) and 12 (7.1%) patients, respectively. The 480 mg Q4W dose was selected as the recommended phase II dose. AMG 404 serum exposure increased approximately dose proportionally. The objective response rate (80% CI) was 19.6% (15.7–24.1) for the overall population and 36.6% (26.4–47.8) and 30.8% (14.2–‍52.3) for cohorts with MSI-H tumours (n=41) and NSCLC/PDL1-H (n=13), respectively. The overall disease control rate (80% CI) was 54.8% (49.5–59.9). The median (80% CI) PFS was 3.7 (3.5–4.5) months for the overall population and 14.8 (9.0–not estimable) and 4.4 (2.2–9.7) months for cohorts with MSI-H tumours and NSCLC/PDL1-H, respectively.Conclusions AMG 404 monotherapy was tolerable at the tested doses, with encouraging antitumour activity observed across tumour types.Trial registration number NCT03853109.

Introduction It is estimated that 10–25% of breast cancer patients have metastatic disease upon diagnosis with roughly 20% having limited metastatic sites. The optimal management of patients with de novo bone-only oligometastatic breast cancer (OMBC), particularly curative-intent approaches, continues to evolve given extremely limited evidence in survival outcomes with this strategy. Methods This was a single-center retrospective review of the survival outcomes and details of treatment of patients with de novo OMBC who received tri-modality treatment with systemic therapy (chemotherapy with or without endocrine treatment and/or HER2-directed therapy), surgery, and radiotherapy to local and metastatic site/s. Progression-free survival (PFS) was defined as the time from initiation of treatment (either surgery, or neoadjuvant systemic therapy) to date of clinical or radiologic progression. Results From January 2014-March 2024, we identified 10 women who fit the inclusion criteria. Seven had isolated bone metastasis, and none had more than 3 metastatic sites. The included cohort had a mean age of 44.2 years. Nine had hormone receptor-positive disease, and 5 were HER2-positive. All patients were discussed in a multidisciplinary meeting. Median PFS by Kaplan-Meier analysis was 40.2 months. Nine patients were still alive at the time of analysis, and 6 of them remain disease free with a median follow-up duration of 30.8 months. Conclusion Patients with de novo bone-only oligometastatic breast cancer seem to benefit from the standard curative-intent tri-modality approach with the addition of ablative radiation to metastatic sites. These patients have a long median PFS and can be rendered disease-free for many years.

INTRODUCTION:The coronavirus disease 2019 (COVID-19) pandemic has resulted in a widespread adoption of telehealth (phone and video consultations) in cancer care worldwide. The aim of this study was to determine patient satisfaction with telehealth consultations with their medical oncologist at a tertiary cancer centre in Sydney, Australia.METHODS:Patients who attended a routine telehealth appointment at the medical oncology outpatient clinic were recruited to complete a questionnaire containing 16 items, each on a 5-point Likert scale regarding satisfaction levels in various aspects of telehealth and their willingness to continue telehealth after the pandemic. Patients were also invited to provide suggestions for improvement.RESULTS:In total, 150 patients were invited to participate, and 103 valid questionnaires were returned. Median age was 63 years (range: 25-90), 49% of patients were male, 63% of patients had advanced cancer and 81% were on active treatment. In total, 95% of participants indicated that they were satisfied (score ≥4) with telehealth. 82% of participants preferred to continue telehealth consultations after the coronavirus disease 2019 pandemic, but ideally with a mix of telehealth and in-person consultations. Phone appointments (vs. video, p < 0.002), patients with advanced cancer (vs. early, p < 0.036) and pre-chemotherapy/immunotherapy/targeted therapy treatment reviews (vs. follow-up appointments, p < 0.001) were significantly associated with a willingness to continue telehealth.DISCUSSION:Patients were overwhelmingly satisfied with telehealth during the study period and were willing to continue telehealth for some appointments beyond the coronavirus disease 2019 pandemic. More research into the effectiveness, safety and implementation of telehealth to compliment traditional face-to-face services for patient-centred cancer care is required.

6048 Background: Survival in recurrent/metastatic HNmSCC remain poor. PD-1 inhibitors have become standard of care, demonstrating improved overall survival and toxicity when compared to chemotherapy and targeted therapy. Biomarkers such as PD-Ligand(L)1 combined proportion score (CPS) remain rudimentary, with CPS >20 showing a response rate of only 23% to pembrolizumab (KEYNOTE-048). We used high-dimensional imaging mass cytometry (IMC) to explore predictive biomarkers in HNmSCC pts receiving PD-1 inhibitor-based therapy. Methods: We retrospectively analysed 27 formalin-fixed paraffin embedded tissue samples from 24 pts prior to receiving PD-1 inhibitor-based therapy between May 2016 – April 2021. Clinicopathological characteristics including PD-L1, p16 status, prior treatment and survival data were collected. Pts were classified into responders (RES, Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 complete response (CR) or partial response (PR), stable disease (SD) >6 months (mths)) and non-responders (non-RES, RECIST SD <6 mths or disease progression (PD)). An antibody panel (n = 40) was created to interrogate specific components of interest within the TME and was analysed by IMC using the HyperionTM Imaging System. Results: Of the 24 patients, 16/24 were male and median age 57.6 year. 8 pts were RES (RECIST CR, n = 1; PR, n = 3; SD > 6 mths, n = 4) and 14 pts were non-RES (RECIST SD < 6 mths, n = 1; PD, n = 11; clinical PD, n = 4). Four patients underwent rapid clinical disease progression prior to progress imaging and were categorised as non-RES. At time of data cut off on January 2024, and 23/24 pts had progressed on treatment. The cellular landscape within the TME was similar, irrespective of the location of the primary and p16 status. However, distinct immune profiles were observed between RES vs non-RES: RES showed higher infiltrates of CD4+ T cells, B cells, PD-1+ CD8+ T cells (P < 0.05) and both central memory and effector memory T cell subsets (p < 0.01). In contrast, non-RES showed high frequencies of CD44+ NK cells. Key cell interactions within the TME identified proliferating malignant squamous cells closely interacting with CD8+ T cells, CD4+ Tregs and endothelial cell in RES but not interacting in non-RES. Further spatial regional analysis identified a distinct tissue architecture with hallmarks of Tertiary Lymphoid-like Structures (TLS), present in higher proportions in RES. RES pts with TLS proportions >20% (n = 3) had a progression free survival of 80.3 mths, 26.8 mths and NE (unrelated death at 15.6 mths). Conclusions: The findings of this study identify mechanisms of PD-1 inhibitor response and resistance in HNmSCC pts, providing a unique opportunity to guide combination strategies and improve outcome.

AMG 256 is a bi-specific, heteroimmunoglobulin molecule with an anti-PD-1 antibody domain and a single IL-21 mutein domain on the C-terminus. Nonclinical studies in cynomolgus monkeys revealed that AMG 256 administration led to the development of immunogenicity-mediated responses and indicated that the IL-21 mutein domain of AMG 256 could enhance the anti-drug antibody response directed toward the monoclonal antibody domain. Anti-AMG 256 IgE were also observed in cynomolgus monkeys. A first-in-human (FIH) study in patients with advanced solid tumors was designed with these risks in mind. AMG 256 elicited ADA in 28 of 33 subjects (84.8%). However, ADA responses were only robust and exposure-impacting at the 2 lowest doses. At mid to high doses, ADA responses remained low magnitude and all subjects maintained exposure, despite most subjects developing ADA. Limited drug-specific IgE were also observed during the FIH study. ADA responses were not associated with any type of adverse event. The AMG 256 program represents a unique case where nonclinical studies informed on the risk of immunogenicity in humans, due to the IL-21-driven nature of the response.

Abstract Breast cancer is a heterogeneous disease at multiple levels, ranging from subtype differences between patients (inter-patient heterogeneity) to the diverse composition of malignant cells, heterogeneity of hormone receptor (HR) expression and cellular makeup within single breast cancer samples (intra-tumour heterogeneity). Despite an increase in the number of effective therapies available, many patients will experience an incomplete treatment response and subsequent relapse. These adverse treatment outcomes may be attributed to the often overlooked but critical factor of cellular heterogeneity. In order to gain deeper insights into intra-tumour heterogeneity, we have applied single-cell technologies on a cohort comprising 250 primary, untreated breast cancers. We have optimized methods for tissue cryopreservation, eliminating the need for fresh sample processing, and multiplex tissue profiling. Together, these are cost-efficient processes that allow for improved handling of small tissue sizes, such as biopsies, and reduce batch effect. To ensure accurate and reliable data processing, we have developed a scalable computational workflow that includes benchmarked methods for sample SNP-demultiplexing, doublet detection, high-resolution cell annotation and cellular integration. Finally, we are extending our existing methods1 to study the cellular heterogeneity of breast cancers. Our method, scSubtyper, explores the phenotypic differences between malignant cells within tumours, by comparing each single cell to distinct features associated with different molecular subtypes and assigning each cell to one of these subtypes. Our previous study1 and preliminary results of this project revealed that over 90% of the samples exhibit a mix of malignant cells of different subtypes, and 50% of samples contain cells that have characteristics of all subtypes, demonstrating cellular heterogeneity exists not only exists between malignant cells, but also within malignant cells of a tumour. Our second approach, known as ecotyping, assesses patterns of cell type frequencies across samples and groups them based on similarity of these co-occurences. Our preliminary results have revealed the existence of 5 ecotypes that lack significant associations with samples clinical subtypes. Applying the same approach exclusively within the HR-positive samples identified 4 ecotypes characterized by distinct abundances of immune and stromal cells. This analysis revealed that ecotypes are not a simple surrogate for clinical and molecular subtypes, but their presence could drive different response to treatment. Together, our high-throughput tissue processing and computational approaches to studying intra-tumour heterogeneity are now being applied to our large, well annotated, clinical cohort. Supported by the preliminary results, we hypothesize that this study will play a vital role in optimizing breast cancer patient stratification to improve treatment management and outcome. 1. Wu, Sunny Z., et al. "A single-cell and spatially resolved atlas of human breast cancers." Nature genetics 53.9 (2021): 1334-1347. Citation Format: Beata Kiedik, Daniel Roden, Kate Harvey, Ghamdan Al-Eryani, Sunny Wu, Mun Hui, Sandra O'Toole, Elgene Lim, Charles Perou, Alex Swarbrick. Exploring cellular heterogeneity of localised breast cancers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-01-09.

6026 Background: The transformed growth factor beta (TGF-β) signaling pathway is dysregulated in carcinogenesis. In NPC patients, upregulation of TGF-β pathway is correlated with disease stage or phenotype due to Epstein-Barr virus (EBV) infection. GFH018, a novel TGF-βRI inhibitor, can inhibit tumor growth through inhibiting the activity of TGF-βRI kinase to block the signal transduction of TGF-β and modulate the tumor immune microenvironment. Preclinical studies showed that GFH018 in combination with PD-1/PD-L1 monoclonal antibody can significantly inhibit tumor growth synergistically. Here we report the preliminary results of combining GFH018 and Toripalimab treating R/M NPC patients (pts). Methods: This is a phase Ib/II study to evaluate the safety and efficacy of the combination of GFH018 and Toripalimab in pts with advanced solid tumors. Patients with RM NPC were enrolled to receive GFH018 80mg twice a day (BID) 14-day-on/14-day-off in combination with Toripalimab 3mg/kg every two weeks. Tumor assessment was performed every 8 weeks per Response Evaluation Criteria in Solid Tumor (RECIST) 1.1. Results: As of 31 Dec 2022, 32 pts with R/M NPC who had progressed on at least one prior line therapy were enrolled. Sixteen (50%) had received ≥3 lines of prior therapies, and 19 (59.4%) had previously received immune checkpoint inhibitors (ICIs) and platinum-based chemotherapies. The median duration of study drug exposure was 7 weeks. Twenty-five pts (78.1%) experienced treatment-related adverse events (TRAEs) of any grades, and 11 pts (34.4%) had ≥ Grade 3. The most common TRAEs (occurring in ≥ 3 pts) were anaemia (n = 6, 18.8%), hyponatraemia (n = 6, 18.8%), rash (n = 6, 18.8%), fatigue (n = 4, 12.5%), white blood cell count decreased (n = 4, 12.5%), aspartate aminotransferase increased (n = 3, 9.4%), back pain (n = 3, 9.4%), decreased appetite (n = 3, 9.4%), hypokalaemia (n = 3, 9.4%), and hypothyroidism (n = 3, 9.4%). As of 18 Jan 2023, among the 27 pts with post-baseline tumor assessments, 8 achieved partial response (PR), and 5 stable disease (SD); the overall response rate (ORR) was 29.6%, and disease control rate (DCR) was 48.1%. Six PR and 2 SD were observed among the 12 pts without prior treatment of ICIs; the ORR was 50%, and DCR was 66.7%. Four pts discontinued treatment without any post-baseline tumor assessments due to AEs or withdrawal of consent, and 1 patient is premature for tumor assessment. Conclusions: GFH018 combined Toripalimab was well tolerated and demonstrated preliminary efficacy in pts with R/M NPC. Specifically, in pts who had not previously received ICIs, promising antitumor activity was observed supporting further investigation to this group of pts. Clinical trial information: NCT04914286 .

INTRODUCTION:Next-generation sequencing (NGS) diagnostics have shown clinical utility in predicting survival benefits in patients with certain cancer types who are undergoing targeted drug therapies. Currently, there are no guidelines or recommendations for the use of NGS in patients with metastatic cancer from an Asian perspective. In this article, we present the Asia-Pacific Oncology Drug Development Consortium (APODDC) recommendations for the clinical use of NGS in metastatic cancers.METHODS:The APODDC set up a group of experts in the field of clinical cancer genomics to (i) understand the current NGS landscape for metastatic cancers in the Asia-Pacific (APAC) region; (ii) discuss key challenges in the adoption of NGS testing in clinical practice; and (iii) adapt/modify the European Society for Medical Oncology guidelines for local use. Nine cancer types [breast cancer (BC), gastric cancer (GC), nasopharyngeal cancer (NPC), ovarian cancer (OC), prostate cancer, lung cancer, and colorectal cancer (CRC) as well as cholangiocarcinoma and hepatocellular carcinoma (HCC)] were identified, and the applicability of NGS was evaluated in daily practice and/or clinical research. Asian ethnicity, accessibility of NGS testing, reimbursement, and socioeconomic and local practice characteristics were taken into consideration.RESULTS:The APODDC recommends NGS testing in metastatic non-small-cell lung cancer (NSCLC). Routine NGS testing is not recommended in metastatic BC, GC, and NPC as well as cholangiocarcinoma and HCC. The group suggested that patients with epithelial OC may be offered germline and/or somatic genetic testing for BReast CAncer gene 1 (BRCA1), BRCA2, and other OC susceptibility genes. Access to poly (ADP-ribose) polymerase inhibitors is required for NGS to be of clinical utility in prostate cancer. Allele-specific PCR or a small-panel multiplex-gene NGS was suggested to identify key alterations in CRC.CONCLUSION:This document offers practical guidance on the clinical utility of NGS in specific cancer indications from an Asian perspective.

Abstract There is strong interest in targeting the androgen receptor (AR) in estrogen receptor (ER) positive breast cancer, but widespread confusion exits as to what therapeutic strategy - agonism or antagonism - is appropriate. Current understanding of AR predominantly stems from the field of prostate cancer, where AR is the key oncogenic driver and therapeutic target. An ensuing assumption is that AR promotes malignancy in breast cancer and should be therapeutically antagonised. However, compelling pre-clinical data to support this assumption is lacking. Since estrogen stimulates and androgen inhibits the development of normal breast tissue, we hypothesized that AR acts as a tumour suppressor in the breast and that AR agonism is the appropriate therapeutic strategy for ER-driven breast cancer. We tested this hypothesis using a large suite of cell line and patient-derived explant (PDE) and xenograft (PDX) models of breast cancer, including those that were resistant to current therapies and those harbouring genomic anomalies of ESR1 associated with treatment-resistant disease. Across the diverse models we found compelling evidence that AR agonism, but not antagonism, potently and durably inhibited tumour growth. A signature of AR activity derived from the xenograft models positively predicted disease survival in multiple large clinical cohorts of ER+ breast cancer, out-performing other breast cancer-specific prognostic signatures. We also show that an AR agonist can be combined with current ER target therapies such as Tamoxifen or a CDK4/6 inhibitor to maximize growth inhibition. Mechanistically, agonist-bound AR opposed ER signalling by repositioning ER and the co-activator p300 in the chromatin landscape, resulting in down-regulation of cell cycle genes. Introduction of an AR DNA binding mutant had no effect on ER signalling or estrogen-stimulated growth in breast cancer cells. As part of this study, we have generated consensus AR cistromes representing ER+ breast cancer cell lines and ER+ tumours that provide a new understanding of AR activity and clearly show differences to those associated with prostate cancer cell lines and tumours. In conclusion, our data provides a compelling biological rationale for AR agonism as a therapeutic strategy in multiple, clinically relevant contexts of ER-positive breast cancer. These findings should dispel widespread confusion over the role of AR in ER-driven breast cancer, an issue that currently hinders progress in leveraging modern AR-targeted therapies (e.g. selective androgen receptor modulators) that lack the undesirable side-effects of androgens for clinical benefit.

Breast cancers are complex cellular ecosystems where heterotypic interactions play central roles in disease progression and response to therapy. However, our knowledge of their cellular composition and organization is limited. Here we present a single-cell and spatially resolved transcriptomics analysis of human breast cancers. We developed a single-cell method of intrinsic subtype classification (SCSubtype) to reveal recurrent neoplastic cell heterogeneity. Immunophenotyping using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) provides high-resolution immune profiles, including new PD-L1/PD-L2+ macrophage populations associated with clinical outcome. Mesenchymal cells displayed diverse functions and cell-surface protein expression through differentiation within three major lineages. Stromal-immune niches were spatially organized in tumors, offering insights into antitumor immune regulation. Using single-cell signatures, we deconvoluted large breast cancer cohorts to stratify them into nine clusters, termed 'ecotypes', with unique cellular compositions and clinical outcomes. This study provides a comprehensive transcriptional atlas of the cellular architecture of breast cancer.

BackgroundParticular breast cancer subtypes pose a clinical challenge due to limited targeted therapeutic options and/or poor responses to the existing targeted therapies. While cell lines provide useful pre-clinical models, patient-derived xenografts (PDX) and organoids (PDO) provide significant advantages, including maintenance of genetic and phenotypic heterogeneity, 3D architecture and for PDX, tumor-stroma interactions. In this study, we applied an integrated multi-omic approach across panels of breast cancer PDXs and PDOs in order to identify candidate therapeutic targets, with a major focus on specific FGFRs.MethodsMS-based phosphoproteomics, RNAseq, WES and Western blotting were used to characterize aberrantly activated protein kinases and effects of specific FGFR inhibitors. PDX and PDO were treated with the selective tyrosine kinase inhibitors AZD4547 (FGFR1-3) and BLU9931 (FGFR4). FGFR4 expression in cancer tissue samples and PDOs was assessed by immunohistochemistry. METABRIC and TCGA datasets were interrogated to identify specific FGFR alterations and their association with breast cancer subtype and patient survival.ResultsPhosphoproteomic profiling across 18 triple-negative breast cancers (TNBC) and 1 luminal B PDX revealed considerable heterogeneity in kinase activation, but 1/3 of PDX exhibited enhanced phosphorylation of FGFR1, FGFR2 or FGFR4. One TNBC PDX with high FGFR2 activation was exquisitely sensitive to AZD4547. Integrated 'omic analysis revealed a novel FGFR2-SKI fusion that comprised the majority of FGFR2 joined to the C-terminal region of SKI containing the coiled-coil domains. High FGFR4 phosphorylation characterized a luminal B PDX model and treatment with BLU9931 significantly decreased tumor growth. Phosphoproteomic and transcriptomic analyses confirmed on-target action of the two anti-FGFR drugs and also revealed novel effects on the spliceosome, metabolism and extracellular matrix (AZD4547) and RIG-I-like and NOD-like receptor signaling (BLU9931). Interrogation of public datasets revealed FGFR2 amplification, fusion or mutation in TNBC and other breast cancer subtypes, while FGFR4 overexpression and amplification occurred in all breast cancer subtypes and were associated with poor prognosis. Characterization of a PDO panel identified a luminal A PDO with high FGFR4 expression that was sensitive to BLU9931 treatment, further highlighting FGFR4 as a potential therapeutic target.ConclusionsThis work highlights how patient-derived models of human breast cancer provide powerful platforms for therapeutic target identification and analysis of drug action, and also the potential of specific FGFRs, including FGFR4, as targets for precision treatment.