Community Cancer Center

3110 Background: Outcomes on tyrosine kinase inhibitor (TKI) treatment in EGFR -mutant non-small cell lung cancer (NSCLC) fall short of the durable benefit observed with next-generation targeted therapies in ALK and ROS1 -driven NSCLC. Novel targeted therapies are needed to address treatment resistance and offer prolonged patient benefit with reduced toxicity. We recently described (AACR 2025) the design and discovery of BH-30643, a first-in-class macrocyclic reversible TKI targeting the active conformation of mutant EGFR and offering potent, mutant-selective EGFR inhibition across classical and non-classical EGFR mutations. Here we study diverse preclinical models to assess the breadth of activity from this novel approach. Methods: Anti-tumor activity of BH-30643 was evaluated in cell-derived xenograft (CDX) or patient-derived xenograft (PDX) tumor models carrying classical or atypical EGFR mutations. CNS activity of BH-30643 was investigated in an intracranial xenograft model. BH-30643 was administered twice daily via oral gavage; osimertinib when used as a comparator was dosed daily. Studies were done with n ≥ 5. The activity of BH-30643 against diverse EGFR exon 20 insertions (ex20ins) was evaluated in 34 engineered Ba/F3 cell lines in cell proliferation assays in vitro. Results: In the PC-9 (exon 19 del) CDX model, BH-30643 led to deep tumor regressions, similar to what was observed with osimertinib at the 25 mg/kg dose level. Similarly deep responses with BH-30643 were observed in double mutant CDX models including those derived from H1975 cells (cis L858R / T790M) and Ba/F3 cells engineered with exon 19 del / T790M. In a triple-mutant PDX model (cis exon 19 del / T790M / C797S) and a Ba/F3 triple-mutant CDX model (cis L858R / T790M / C797S), deep responses were observed with BH-30643 while osimertinib demonstrated no anti-tumor effect. BH-30643 activity was also evident in the HCC827-luc (exon 19 del) intracranial xenograft model with 90% tumor reduction. In two Ba/F3 CDX models carrying atypical mutations (cis G719A / S768I and cis G719A /L861Q), BH-30643 maintained strong anti-tumor activity. Finally, we explored the activities of BH-30643 against 34 different EGFR ex20ins in engineered Ba/F3 cell lines and BH-30643 showed anti-cell proliferation activity with a median IC 50 value of 6.06 nM. Conclusions: These preclinical studies demonstrate broad activity of BH-30643 against classical and atypical EGFR activating mutations, EGFR ex20ins, as well as acquired resistance EGFR mutations. Such an "OMNI-EGFR" inhibitor may be able to overcome some of the limitations of earlier agents. Supported by favorable ADME and preclinical safety profiles, BH-30643 is now being assessed in a first-in-human study in locally advanced or metastatic NSCLC harboring EGFR and/or HER2 mutations (NCT06706076, SOLARA).

Triple-negative breast cancer (TNBC) disproportionately affects Black women. Immunotherapy improves outcomes in early-stage TNBC (esTNBC) and metastatic TNBC (mTNBC). However, racial and ethnic disparities in immunotherapy receipt and its potential association with oncologic outcomes are unknown. To examine trends and racial and ethnic disparities in immunotherapy receipt and differences in pathologic complete response (pCR) and overall survival (OS) in TNBC. This retrospective cohort study analyzed the 2019-2021 National Cancer Database. Data were analyzed from April 1 to August 31, 2024. The esTNBC cohort included patients with stage II to III TNBC treated with neoadjuvant therapy in 2021. The mTNBC cohort included patients with stage IV TNBC treated from 2019 to 2021, with all patients having received chemotherapy with or without immunotherapy. Immunotherapy use, pCR, and OS with respect to race and ethnicity. A total of 10 724 patients with TNBC were included (mean [SD] age, 56.1 [13.7] years; 473 [4.4%] Asian or Pacific Islander, 2569 [24.0%] Black, 981 [9.1%] Hispanic, 6465 [60.3%] White, and 236 [2.2%] other). Immunotherapy use increased from 5.5% in 2017 to 38.8% in 2021 for mTNBC and from 4.2% in 2017 to 48.0% in 2021 for esTNBC. Of 7655 cases of esTNBC diagnosed in 2021, immunotherapy use was lower in Black patients (788 of 1715 [45.9%]), but this difference was not significant after adjusting for insurance status, treatment facility type, and other key variables. Among patients with esTNBC receiving immunotherapy, pCR was similar by race and ethnicity. Of 3069 cases of mTNBC diagnosed from 2019 to 2021, immunotherapy use was higher in Asian or Pacific Islander patients (36 of 97 [37.1%]) and lower in Black patients (238 of 848 [28.1%]). Black patients had lower odds of immunotherapy receipt than White patients (adjusted odds ratio, 0.63; 95% CI, 0.49-0.80) even after controlling for confounders. Among patients receiving immunotherapy, OS was similar between Black and White patients (adjusted hazard ratio, 0.92; 95% CI, 0.64-1.32). In this cohort study of TNBC, Black patients with mTNBC were less likely to have received immunotherapy, even after controlling for socioeconomic factors. In both esTNBC and mTNBC cohorts, patients who received immunotherapy attained similar outcomes across racial and ethnic groups; thus, efforts should be made to ensure equal access to immunotherapy.

BackgroundUncontrolled proliferation of metastatic solid tumors accounts for most cancer-related deaths. Metastatic tumors in the brain exemplify several key difficulties associated with researching and treating metastatic disease, including poor tissue penetration by anti-neoplastic drugs and tight control of infiltrating immune cell function. Potentiation of brain-infiltrating effector immune cells represents a favorable strategy for the clinical management of brain metastasis. Natural killer (NK) cells have shown particular promise in this regard.1 2 Accumulating clinical and pre-clinical evidence supports a vital role for NK cells in anti-metastatic immunity and has prompted the rapid development of both NK cell engagers and adoptive NK cell transplants—both of which have entered clinical trials.2–11 Our work seeks to define NK cell anti-metastatic function in the brain with the goal of enhancing NK cell-mediated tumor control.MethodsUsing cellular and molecular methods, we characterize the infiltration and function of NK cells and closely-related ILC1 cells in the brain metastatic microenvironment. We use flow cytometry to characterize tumor infiltration kinetics, antibody-mediated depletion and genetic knockout models to assess the individual contributions of NK cells and ILC1s, scRNA-seq to compare NK cell and ILC1 function and phenotype in the brain with that observed in peripheral tissues, and functional assays to identify strategies for NK cell potentiation in the brain.ResultsWe observe that NK cells rapidly infiltrate metastatic brain lesions but fail to robustly control metastatic outgrowth. scRNA-seq suggests functional deficits in brain-infiltrating NK cells relative to those infiltrating other organs. Cytokine supplementation suggests that NK cell deficits in the brain may be correctable. Our ongoing work seeks to explore effective strategies for NK cell enhancement in the response to brain metastasis.ConclusionsNK cells and closely-related ILC1s play crucial roles in the control of the metastatic spread of cancer. Our work describes the response of these cell types to metastatic colonization of the brain and suggests that NK cell functional deficiencies may be therapeutically targeted to improve metastatic control in the brain. This work maintains an end goal of rapid clinical translation of our findings in the adoptive NK cell therapy space.ReferencesSedgwick AJ, Ghazanfari N, Constantinescu P, Mantamadiotis T, Barrow AD. The role of NK cells and innate lymphoid cells in brain cancer. Frontiers in Immunology 2020;11.López-Soto A, Gonzalez S, Smyth M J and Galluzzi L. Control of Metastasis by NK Cells. Cancer Cell 2017;32:135–154.Schuijs MJ, et al. ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung. Nat Immunol 2020;21:998–1009.Malladi S, et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 2016;165:45–60.Evans KT, et al. Microglia promote anti-tumour immunity and suppress breast cancer brain metastasis. Nat Cell Biol 2023;25:1848–1859.Cichocki F, et al. iPSC-derived NK cells maintain high cytotoxicity and enhance in vivo tumor control in concert with T cells and anti–PD-1 therapy. Science Translational Medicine 2020;12:eaaz5618.Benbenishty A, et al. Prophylactic TLR9 stimulation reduces brain metastasis through microglia activation. PLOS Biology 2019;17:e2006859.Chiossone L, Dumas P-Y, Vienne M and Vivier E. Natural killer cells and other innate lymphoid cells in cancer. Nat Rev Immunol 2018;18:671–688.Ma D, Hernandez G, et al. Patient-derived xenograft culture-transplant system for investigation of human breast cancer metastasis. Commun Biol 2021;4:1268.Meraz IM, et al. An improved patient-derived xenograft humanized mouse model for evaluation of lung cancer immune responses. Cancer Immunol Res 2019;7:1267–1279.Nguyen R, et al. Next-generation humanized patient-derived xenograft mouse model for pre-clinical antibody studies in neuroblastoma. Cancer Immunol Immunother 2021;70:721–732.Ethics ApprovalThe work described in this abstract was conducted with the approval of the UCI Institutional Animal Care and Use Committee and was performed under the supervision of the UCI University Laboratory Animal Resource.

Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C-mutant non-small cell lung carcinoma (NSCLC) accounts for approximately 10-13% of advanced nonsquamous NSCLC cases in Western populations, presenting a significant therapeutic challenge owing to the difficulty of directly targeting KRAS. Adagrasib, an oral small-molecule covalent inhibitor, irreversibly and selectively targets KRASG12C in its inactive state. It received accelerated Food and Drug Administration (FDA) approval on December 12, 2022, following the KRYSTAL-1 Phase II trial. The Phase III KRYSTAL-12 trial demonstrated that adagrasib significantly improved median progression-free survival (mPFS) compared with docetaxel (HR, 0.58; 95% CI: 0.45-0.76; P<0.0001) and increased the intracranial objective response rate (ORR) to 40% in the central nervous system (CNS) evaluable population. This paper evaluates the clinical efficacy of adagrasib in KRAS G12C-mutated advanced NSCLC discussing its potential advantages over other inhibitors such as sotorasib. Despite not reaching the 6-month mPFS benchmark, adagrasib offers significant clinical benefits, particularly for the management of CNS metastases. In this pros and cons debate, we argue that adagrasib has broken the KRAS G12C enigma code in NSCLC.

To assess trends and rural-urban disparities in palliative care utilization among patients with metastatic breast cancer. We analyzed data from the 2004-2019 National Cancer Database. Palliative care services, including surgery, radiotherapy, systemic therapy, and/or other pain management, were provided to control pain or alleviate symptoms; utilization was dichotomized as "yes/no." Rural-urban residence, defined by the US Department of Agriculture Economic Research Service's Rural-Urban Continuum Codes, was categorized as "rural/urban/metropolitan." Multivariable logistic regression was used to examine rural-urban differences in palliative care use. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated. Of 133,500 patients (mean age 62.4 [SD=14.2] years), 86.7%, 11.7%, and 1.6% resided in metropolitan, urban, and rural areas, respectively; 72.5% were White, 17.0% Black, 5.8% Hispanic, and 2.7% Asian. Overall, 20.3% used palliative care, with a significant increase from 15.6% in 2004-2005 to 24.5% in 2008-2019 (7.0% increase per year; p-value for trend <0.001). In urban areas, 23.3% received palliative care, compared to 21.0% in rural and 19.9% in metropolitan areas (p<0.001). After covariate adjustment, patients residing in rural (AOR=0.84; 95% CI: 0.73-0.98) or metropolitan (AOR=0.85, 95% CI: 0.80-0.89) areas had lower odds of having used palliative care than those in urban areas. In this national, racially diverse sample of patients with metastatic breast cancer, the utilization of palliative care services increased over time, though remained suboptimal. Further, our findings highlight rural-urban disparities in palliative care use and suggest the potential need to promote these services while addressing geographic access inequities for this patient population.

One of the most recent advancements in NSCLC was the approval of immunotherapy in the adjuvant setting. Both atezolizumab and pembrolizumab have been approved for the use in early stage NSCLC patients post resection. As it broadens the options for our patients, multiple approvals in the same setting are generally welcomed. However, there were important differences in the two studies that led to the approvals and the data could be confusing. Here we review IMpower010, the study that led to the first approval of atezolizumab in the adjuvant setting with comparison to the Keynote-091 study evaluating pembrolizumab in the adjuvant setting, gaining the most recent FDA approval for adjuvant use in early stage NSCLC.

We present here a 66-year-old Caucasian male whose persistent abdominal pain thought to be due to appendicitis and associated acute splanchnic thrombosis. He was initially managed with antibiotics and anticoagulation. But further work up revealed a low-grade appendiceal mucinous neoplasm causing the splanchnic vein thrombosis. Additionally, diagnosis and management of this rare tumor and appropriate work up for splanchnic thrombosis will be briefly reviewed here.

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; To determine whether mTORC2 and rapamycin-insensitive (RI)-mTORC1 complexes are present in acute myeloid leukemia (AML) cells and to examine the effects of dual mTORC2/mTORC1 inhibition on primitive AML leukemic progenitors.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; Combinations of different experimental approaches were used, including immunoblotting to detect phosphorylated/activated forms of elements of the mTOR pathway in leukemic cell lines and primary AML blasts; cell-proliferation assays; direct assessment of mRNA translation in polysomal fractions of leukemic cells; and clonogenic assays in methylcellulose to evaluate leukemic progenitor-colony formation.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; mTORC2 complexes are active in AML cells and play critical roles in leukemogenesis. RI-mTORC1 complexes are also formed and regulate the activity of the translational repressor 4E-BP1 in AML cells. OSI-027 blocks mTORC1 and mTORC2 activities and suppresses mRNA translation of cyclin D1 and other genes that mediate proliferative responses in AML cells. Moreover, OSI-027 acts as a potent suppressor of primitive leukemic precursors from AML patients and is much more effective than rapamycin in eliciting antileukemic effects &lt;i&gt;in vitro&lt;/i&gt;.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Dual targeting of mTORC2 and mTORC1 results in potent suppressive effects on primitive leukemic progenitors from AML patients. Inhibition of the mTOR catalytic site with OSI-027 results in suppression of both mTORC2 and RI-mTORC1 complexes and elicits much more potent antileukemic responses than selective mTORC1 targeting with rapamycin. &lt;i&gt;Clin Cancer Res; 17(13); 4378–88. ©2011 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;