Early Clinical Data Research Articles

Cancer Cachexia and Antitumor Immunity: Common Mediators and Potential Targets for New Therapies.

Cancer cachexia syndrome (CCS) is a multifactorial metabolic syndrome affecting a significant proportion of patients. CCS is characterized by progressive weight loss, alterations of body composition and a systemic inflammatory status, which exerts a major impact on the host’s innate and adaptive immunity. Over the last few years, the development of immune checkpoint inhibitors (ICIs) transformed the treatment landscape for a wide spectrum of malignancies, creating an unprecedented opportunity for long term remissions in a significant subset of patients. Early clinical data indicate that CCS adversely impairs treatment outcomes of patients receiving ICIs. We herein reviewed existing evidence on the potential links between the mechanisms that promote the catabolic state in CCS and those that impair the antitumor immune response. We show that the biological mediators and processes leading to the development of CCS may also participate in the modulation and the sustainment of an immune suppressive tumor microenvironment and impaired anti-tumor immunity. Moreover, we demonstrate that the deregulation of the host’s metabolic homeostasis in cancer cachexia is associated with resistance to ICIs. Further research on the interrelation between cancer cachexia and anti-tumor immunity is required for the effective management of resistance to immunotherapy in this specific but large subgroup of ICI treated individuals.

IMMU-16. Next-generation CAR T-cells targeting IL13RA2 and secreting IL-15 achieve durable tumour clearance in pre-clinical model of diffuse midline glioma

T-cells engineered with a chimeric antigen receptor (CAR) to acquire tumour specificity provide a possible new treatment approach for childhood brain tumours. Durable clinical remissions have been achieved with CD19-directed CAR T-cells in refractory B-cell malignancies including control of leptomeningeal disease and parenchymal deposits. Early clinical data of CAR-T cells in adult glioblastoma and diffuse midline glioma (DMG) further support the rationale for development of CAR-T cell therapy for paediatric high-grade gliomas (pHGG) and other high-risk childhood brain tumours. IL13RA2 provides a suitable CAR target. It is expressed in the majority of pHGG including DMGs while expression is absent on normal (paediatric) brain tissue. Early results with CAR T-cell therapy for adult HGG has shown that IL13RA2 can be safely targeted, and potent anti-tumour activity is possible. However, responses are variable and ultimately transient. This is likely due to the immunosuppressive environment encountered by CAR T-cells at tumour sites which hampers persistent tumour-directed immunity. Here we develop a next generation CAR approach engineering T-cells with both a CAR and a cytokine signal which supports persistent anti-tumour immunity. We have generated novel IL13RA2-specific antibodies and used these to construct CARs. Using a functional screening approach assessing target-specific cytolytic function, T-cell proliferation and cytokine release, we selected the optimal IL13RA2-CAR design. Then, we generated a next generation CAR construct co-expressing inflammatory cytokine IL-15 with the IL13RA2-CAR. In a PDX model of DMG, T-cells transduced with IL13RA2-CARIL-15, in contrast to IL13RA2-CAR alone, induced long-term tumour clearance. Further in vitro testing of IL13RA2-CARIL-15 showed enhanced proliferation and resistance to immune-suppressive secreted factors such as TGF-β. In conclusion, co-expression of IL-15 with IL13RA2-CAR enhances CAR T-cell proliferation and in vivo persistence and achieves durable tumour clearance. IL13RA2-CARIL-15 is being translated into a phase I clinical trial for patients with DMG.

A phase II study of stereotactic body radiotherapy (SBRT) combined with sintilimab in patients with recurrent or oligometastatic hepatocellular carcinoma (HCC).

4071 Background: SBRT is an emerging treatment option for oligometastatic cancer disease. Preclinical studies have shown the synergistic effects between the radiotherapy and immunotherapy. Early clinical data also suggested that immunotherapy might augment the local effects of radiotherapy and decrease metastatic recurrence. This study aimed to evaluate the efficacy and safety of SBRT combined with sintilimab (a PD-1 antibody) in patients with recurrent or oligometastatic HCC. Methods: In this single arm, phase II study (NCT03857815), eligibility criteria included Pts with recurrent or oligometastatic HCC (defined as ≤5 metastatic/recurrent lesions), Child-Pugh class A, ECOG PS ≤ 1. Pts received sintilimab 200 mg IV Q3W for up to 12 months, progressive disease, unacceptable toxicity, or withdrawal. SBRT to all lesions was started at cycle 1 day 1. Primary endpoint was progression free survival (PFS) per RECIST 1.1. Secondary endpoints included safety, objective response rate (ORR), disease control rate (DCR) and overall survival (OS). Results: At data cutoff (Dec 28th, 2021), 25 pts with 32 lesions were treated with SBRT + Sintilimab. SBRT was delivered at a median dose of 54 Gy (range 48-60) in 6 fractions (range 6-10) and the median follow-up time was 16.9 months (range 3.9-32.1). In those 25 evaluable pts, median age was 64 years (range 37-77), 24 (96%) were male, 24 (96%) were HBV+, 6 (24%) had extrahepatic metastasis, most pts had prior ≥2 local therapies. The confirmed ORR was 96% (24/25) according to RECIST 1.1 with 18pts CR and 6pts PR. 6-mo and 12-mo PFS rate was 100% and 70% (95%CI, 52.3%-93.6%), respectively.12-mo local control rate was 100%. Median PFS and OS was still not mature. Treatment-related adverse events (TRAEs) occurred in 14 pts (56%). Most common TRAEs were rash (16%), platelet count decreased (12%), myositis (8%). Grade 3 TRAEs (myositis) occurred in 1pt (4%). There were no grade 4-5 TRAEs. TRAEs led to discontinuation in 6 pts (24%). SAE were myocarditis (1pt Grade1), viral hepatitis (1pt Grade 3, treatment-independent) and upper gastrointestinal haemorrhage (1pt Grade 3, PD related). Conclusions: The combination of SBRT with Sintilimab was tolerable and showed an encouraging ORR of 96% in pts with recurrent or oligometastatic HCC. Longer follow up is required to further evaluate the efficacy and safety. Clinical trial information: NCT03857815.

Activity and biophysical properties related to clinical evaluation of a first-in-class EHL ROR1xCD3 T Cell Engager.

e14505 Background: NVG-111, a T cell engager (TCE) targeting ROR1 and CD3, is in clinical development for the treatment of Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Leukemia (MCL). This 55KDa molecule consisting of humanised tandem scFvs is administered into patients as a continuous intravenous infusion. The intrinsically short half-life of NVG-111 has its advantages, such as rapid management of CRS by cessation of infusion. Early safety and efficacy clinical data supports the development of an extended half-life (EHL) ROR1xCD3 TCE for ease of administration and convenience for patients, building on the favorable activity and biophysical attributes of NVG-111. A next generation therapy possessing such an EHL has potential to improve patient experience by offering a different drug administration paradigm. Methods: Several formats were designed and evaluated, incorporating different EHL technology solutions by increasing the size and enabling FcRn-mediated recycling. EHL TCEs and non-EHL TCEs were cloned in-format with Fc, HSA, or an HSA binding moiety into a suitable expression vector. The resultant clones were expressed using Expi293 cells and the potency of TCEs were evaluated by co-culture assays using MCL derived JeKo-1 target cells and T cells from healthy donor PBMCs. Cytotoxic responses and T cell activation as determined by CD69 expression were measured by flow cytometry. T cell activation was also assessed by measuring CD3 signalling in a reporter gene assay. Biophysical properties were evaluated by determining the post-purification expression titer, the aggregation profile using analytical SEC, and the impact of stability challenge in formulation buffer and serum on target cell binding and activity. Results: Reformatting NVG-111 into an IgG-like heterodimeric bispecific scFv-Fc resulted in loss of potency, which may be due to a change in geometry of binding and/or poorer target engagement. Activity and expression titer were also deleteriously affected by directly fusing NVG-111 to human serum albumin (HSA), or to an HSA binding moiety. Fusing NVG-111 directly to Fc resulted in maintained potency in cytotoxicity and T cell activation assays, the expression titer of parental NVG-111, and exhibited very low levels of aggregation. Stability studies performed in formulation buffer and in human serum showed that NVG-111-Fc was at least as stable as parent. Furthermore, other studies with this molecular format indicate that the half-life in mice is comparable to a heterodimeric bispecific scFv-Fc. Conclusions: NVG-111 has been successfully engineered into an EHL format that increased the molecular size and has the potential to engage in FcRn-mediated recycling. This format maintains functional activity, is stable, and expresses well with a favorable aggregation profile. Further molecular refinements are being actively evaluated in readiness for IND enabling studies.

Early clinical safety and pharmacokinetics data of DZD1516, an BBB-penetrant selective HER2 inhibitor for the treatment of HER2-positive metastatic breast cancer.

1038 Background: Patients with HER2+ metastatic breast cancer (MBC) are at high risk of developing central nervous system metastases. DZD1516 is a reversible HER2-specific tyrosine kinase inhibitor (TKI) with full blood-brain barrier (BBB) penetration. Here we report the preliminary safety and PK data from the ongoing phase 1 study (NCT04509596) in patients with HER2+ MBC who relapsed from multiple prior treatments. Methods: Eligible patients received single oral dosing of DZD1516 on C0D1 and then twice daily (BID) oral dosing from C1D1 in a continuous 21-day cycle until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective is to investigate the safety and PK of DZD1516 as a single agent. Results: As of 17 January 2022, DZD1516 was explored in 21 HER2+ MBC patients from the USA and China. DZD1516 was well tolerated at doses < 300 mg, BID. Two DLT events were reported in the 300 mg cohort. In all cohorts, 20 (95.2%) patients reported treatment-emergent adverse events (TEAEs), and 3 (14.3%) patients reported grade 3 drug-related TEAE. Two patients had dose interruption and one patient had dose reduction due to TEAE, all in the 300 mg cohort. Majority of TEAEs were reversible. The longest treatment duration was > 3 months. In all cohorts, the most common (> 20%) TEAEs included headache (42.9%), vomiting (38.1%), nausea (23.8%) and hemoglobin decreased (23.8%). At doses < 300 mg, there is no diarrhea or rash reported. PK data showed that combined exposure of DZD1516 and its active metabolite DZ2678 increased in a dose-proportional manner across the dose ranges. Elimination half-life was about 15-19 hrs. About 2-fold accumulation of DZD1516 in AUC was observed on multiple doses. In vitro, both DZD1516 and DZ2678 showed good permeability, and were not substrates of P-gp and BCRP. In patients, Kpuu,CSF of DZD1516 and DZ2678 was around 2.13 and 0.66, respectively, suggesting good CNS penetration. At the time of data cutoff, 16 patients had at least one post treatment anti-tumor assessment. With a median of 7 lines of prior treatment, the best anti-tumor response was stable disease. Conclusions: Preliminary clinical data showed that DZD1516 is a full BBB-penetrant HER2 TKI, with good safety profile. Consistent with its high selectivity, no wide type EGFR related AEs have been reported. Further evaluation of its safety and efficacy is ongoing. Clinical trial information: NCT04509596. [Table: see text]

Role of anakinra in the management of icans after CAR T-cell therapy for lymphoma.

e19506 Background: Chimeric antigen receptor (CAR) T-cell immunotherapy is a revolutionary treatment modality which has gained attention for its potential in treating multiple refractory hematological malignancies. Significant toxicities associated with CAR T- cell therapy remain a major concern. Cytokine release syndrome (CRS) and Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) are seen early on post CAR-T cell therapy. To date, the treatment of ICANS has largely been limited to supportive care and corticosteroids. More recently, some early clinical data investigated the use of Anakinra as a promising agent in prevention and treatment of severe ICANS. Methods: We analyze three cases in which Anakinra was used to treat high-grade ICANS concurrently with high dose steroids. Results: A 51-year-old woman with high grade DLBCL and secondary CNS involvement was treated with Tisagenlecleucel CAR-T therapy. On day 2, patient became altered and was diagnosed with ICANS Grade II. High dose steroids were started leading to resolution of ICANS. However, patient’s mentation worsened by day 7, progressing to ICANS Grade IV by day 8, and Anakinra 100 mg IV was added to the steroid regimen. By day 11, after 4 doses of Anakinra, patient’s neurotoxicity completely resolved. Patient achieved a PR by day 30 after CAR-T cell infusion. In the second case, a 65-year-old man with DLBCL and leptomeningeal involvement developed ICANS Grade II on day 1 after Tisagenlecleucel CAR-T therapy and was started on high dose steroids. By day 4, neurotoxicity worsened and progressed to ICANS Grade IV. On day 5 patient was transferred to ICU for a mechanical ventilation, and Anakinra 100 mg IV was added and continued daily for 7 days. By day 12, neurotoxicity improved to ICANS grade II and patient was extubated. Meanwhile, high dose steroids were tapered. His condition acutely worsened by day 19, prompting transfer to the ICU and re-initiation of Anakinra concurrently with steroids. His family decided against further escalation of care on day 22. Patient was transitioned to comfort care and died 23 days post CAR-T cell infusion. In the third case, a 65-year-old man with mantle cell lymphoma was treated with Brexucabtagene autoleucel CAR-T therapy. On day 8, patient developed ICANS Grade I which rapidly progressed to Grade IV. High dose steroids were started and ICANS improved to Grade II on Day 9. However, on Day 10 patient’s mentation again worsened and one dose of Anakinra 100mg IV was added to the steroid regimen. By day 11, ICANS completely resolved, and patient was ultimately discharged home on day 15. Patient was able to achieve interval CR by day 30 after CAR-T cell infusion. Conclusions: In the reported cases, ICANS improved following administration of Anakinra, adding support to the idea that Anakinra may be beneficial in treatment of high-grade ICANS. Future studies are needed to better understand the overall efficacy and the ideal timeline for administration.

A two-part, phase II, multi-center study of the ERK inhibitor ulixertinib (BVD-523) for patients with advanced malignancies harboring MEK or atypical BRAF alterations (BVD-523-ABC).

TPS3172 Background: Ulixertinib (BVD-523) is a small molecule inhibitor of extracellular signal-regulated kinases 1/2 (ERK1/2) in development as a novel anti-cancer drug. Early clinical data demonstrated anti-tumor activity, especially for patients with tumors harboring atypical BRAF or MEK1/2 alterations (Sullivan et al., Cancer Discov. 2018;8(2):184-195). Atypical BRAF (non-V600) alterations can be categorized according to characteristics of molecular signaling (Class II or III), are seen in approximately 3% of all human cancers, and there are currently no approved therapies for this indication. Similar to atypical BRAF alterations, the incidence of MEK1/2 alterations are rare in human tumors (< 1 %). Preclinical data have demonstrated activity of ulixertinib in MEK mutant models. Ulixertinib has FDA fast-track designation for patients with solid tumors, other than CRC, with specific BRAF mutations (G469A, L485W, or L597Q). Designed with intent to register, the BVD-523-ABC clinical trial will continue evaluation of ulixertinib in patients with tumors harboring any atypical BRAF or MEK1/2 alteration (NCT04488003). Methods: This multi-center, phase II study, will be conducted in two parts and assess the clinical benefit, safety, pharmacokinetics, and pharmacodynamics of ulixertinib in patients with advanced malignancies. Ulixertinib will be administered at the RP2D of 600 mg BID for 28-day treatment cycles. Eligible patients will have locally advanced or metastatic cancer which progressed following standard systemic therapies, or for which the patient is not a candidate or refused systemic therapy. Planned correlative analyses include reverse phase protein array and transcriptomics of tumor tissue. Part A is open-label and tumor agnostic, except for group 4 and 6 (CRC patients only). Patients will enroll into one of six groups based on BRAF (groups 1-4) or MEK1/2 (groups 5-6) tumor alteration (38 patients per group). Overall response rate (ORR) is the primary endpoint for Part A, with secondary endpoints including duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Part B is tumor histology specific. Patients will be randomized to receive either ulixertinib or physician's choice of treatment in a 2:1 ratio. Up to three specified tumor histologies will be defined, guided by available Part A data (n = 80-100 per histology). The primary endpoint of Part B is PFS, and secondary endpoints include OS, ORR, and DOR. This study has enrolled 43 patients of the planned 228 in Part A at the time of abstract submission. Clinical trial information: NCT04488003.

From COVID-19 Treatment to Miracle Cure

From COVID-19 Treatment to Miracle Cure

Focal prostate cancer therapy in the era of multiparametric MRI: a review of options and outcomes.

The goal of prostate cancer focal therapy is to achieve oncologic control while reducing the rate of adverse events associated with whole-gland treatments. Numerous focal therapy modalities are currently available with early data demonstrating highly variable rates of cancer control and preservation of sexual/urinary function. All English language clinical trial publications evaluating various focal therapies for localized prostate cancer were reviewed. The literature search was limited to studies from the modern era of MRI-guided treatment, as MRI is hypothesized to improve tumor localization and targeting. Primary outcomes were post-treatment cancer-free rates, in-field/out-of-field recurrence rates, and rates of conversion to radical therapy. Secondary outcomes were related to functional status and adverse events. Numerous focal therapies were identified with clinical data including high-intensity focused ultrasound, transurethral ultrasound ablation, focal laser ablation, focal cryotherapy, irreversible electroporation, and photodynamic therapy. Recurrence rates among all technologies were low to moderate (0-51%) and rates of freedom from radical treatment were highly variable (46-98%). Rates of erectile dysfunction and incontinence generally ranged from 0 to 44% and 0 to 12%, respectively, with variability between focal therapy modalities. Caution should be exercised when comparing studies as outcomes are strongly associated with patient selection. No individual focal therapy is currently recommended by society guidelines. Randomized controlled trials are ongoing in search of a standard of care. For localized MRI-visible prostate cancer, early clinical trial data demonstrate that focal therapy can provide good to moderate cancer control while having preferable side effect profiles compared to whole-gland treatments. While current studies do not make head-to-head comparisons between technologies, early data suggest a potential for these technologies to provide adequate cancer control in a well-selected patient population. The oncologic outcomes of some focal therapies appear promising; however, longer-term follow-up data are needed to assess the durability of early outcomes.

Emerging strategies for TNBC with early clinical data: new chemoimmunotherapy strategies

The use of immune checkpoint inhibitors in combination with chemotherapy for the treatment of triple-negative breast cancer is becoming more widespread as efficacy data accumulates. However, outcomes remain less than optimal and not all patients benefit from treatment. The aim of this article is to review the emerging chemoimmunotherapy strategies for triple-negative breast cancer. Searches were undertaken on Pubmed and Clinicaltrials.gov for relevant publications and trials. Preclinical and clinical data have provided insights into the differing immunomodulatory effects of chemotherapy agents, highlighting the immunostimulatory properties of anthracyclines. Mechanisms of resistance to immune checkpoint inhibition are discussed and the potential role of phosphatidylinositol 3-kinase (PI3K)/AKT and MAPK/ERK kinase (MEK) inhibitors in overcoming resistance. Finally, the emerging therapeutic class of antibody-drug conjugates for triple-negative breast cancer in combination with immune checkpoint inhibitors is reviewed. The type and sequence of chemotherapy agents play an important role in optimising the response to immune checkpoint inhibitors. Antibody-drug conjugates in combination with immune checkpoint inhibitors are a promising area of development.

Predictors of Mechanical Ventilation in Guillain-Barré Syndrome with Axonal Subtypes.

The early clinical predictors of respiratory failure in Latin Americans with Guillain-Barré syndrome (GBS) have scarcely been studied. This is of particular importance since Latin America has a high frequency of axonal GBS variants that may imply a worse prognosis. We studied 86 Mexican patients with GBS admitted to the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, a referral center of Mexico City, to describe predictors of invasive mechanical ventilation (IMV). The median age was 40 years (interquartile range: 26-53.5), with 60.5% men (male-to-female ratio: 1.53). Most patients (65%) had an infectious antecedent (40.6% gastrointestinal). At admission, 38% of patients had a Medical Research Council (MRC) sum score <30. Axonal subtypes predominated (60.5%), with acute motor axonal neuropathy being the most prevalent (34.9%), followed by acute inflammatory demyelinating polyneuropathy (32.6%), acute motor sensory axonal neuropathy (AMSAN) (25.6%), and Fisher syndrome (7%). Notably, 15.1% had onset in upper limbs, 75.6% dysautonomia, and 73.3% pain. In all, 86% received either IVIg (9.3%) or plasma exchange (74.4%). IMV was required in 39.5% patients (72.7% in AMSAN). A multivariate model without including published prognostic scores yielded the time since onset to admission <15 days, axonal variants, MRC sum score <30, and bulbar weakness as independent predictors of IMV. The model including grading scales yielded lower limbs onset, Erasmus GBS respiratory insufficiency score (EGRIS) >4, and dysautonomia as predictors. These results suggest that EGRIS is a good prognosticator of IMV in GBS patients with a predominance of axonal electrophysiological subtypes, but other early clinical data should also be considered.

Abstract P2-13-43: Preclinical and early clinical safety and pharmacokinetics data of DZD1516, an BBB-penetrant selective HER2 inhibitor for the treatment of HER2 positive metastatic breast cancer

Abstract Background: Patients with HER2 positive (HER2+) metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases, which is associated with poor prognosis. DZD1516 is designed as a reversible and selective HER2 kinase inhibitor with full blood-brain barrier (BBB) penetration. This compound is currently in phase 1 clinical development in patients with HER2+ MBC (NCT04509596). Here we report the preclinical and preliminary safety and pharmacokinetics (PK) data from the ongoing clinical study. Methods: The cellular activity of DZD1516, including pHER2 modulation and anti-proliferation, was evaluated in a panel of cell lines expressing HER2 or wild type EGFR. The ability of DZD1516 to cross BBB was assessed in both rat and monkey by measuring unbound brain-to-plasma partition ratio (Kpuu,brain ) and unbound CSF-to-plasma partition ratio (Kpuu,CSF). The in vivo anti-tumor activities of DZD1516 alone or in combination with other anti-cancer agents were evaluated in multiple xenograft mouse models including subcutaneous, brain metastasis (BM) and leptomeningeal metastasis (LM) models. The PK and pharmacodynamics (PD) correlation was also investigated. The phase 1 clinical study included monotherapy dose escalation of DZD1516 and in combination with other anti-cancer agents. Results: DZD1516 inhibited pHER2 with IC50 of 4.4 nM. It showed over 300-fold selectivity between pHER2 in cells expressing HER2 and pEGFR in cells expressing wild type EGFR. DZD1516 potently inhibited HER2+ tumor cell proliferation with GI50 of around 20 nM. In vivo, DZD1516 induced profound tumor regression in BT474 subcutaneous, BM and LM xenograft models. A positive correlation between plasma concentration of DZD1516 and pHER2 inhibition in tumor tissue was detected. The measured Kpuu,CSF in rat and monkey were 0.76 and 1.4, respectively.As of June 15, 2021, DZD1516 was explored at 25 mg, 50 mg and 100 mg twice daily with oral administration in eight HER2+ MBC patients from the USA and China. Patient demographics are summarized in Table 1. All patients had prior anti-HER2 antibody and chemotherapy treatment. Majority of patients (75%) also had prior anti-HER2 small molecule treatment. DZD1516 was well tolerated at the doses tested with no dose limiting toxicities observed. The safety data are summarized in Table 2. Drug exposure of DZD1516 increased in a dose proportional manner, with a half-life of around 14.5-19.5 hours and around 1.68 to 2.46-fold accumulation, respectively for single and repeat dosing. In patients with BM, Kpuu,CSF was around 1.82 and 0.78 for DZD1516 and its active metabolite DZ2678, respectively. Patient enrollment is ongoing. The updated data will be presented at the meeting. Conclusion: Preclinical and preliminary clinical data showed that DZD1516 is a full BBB-penetrant HER2 inhibitor, with excellent safety profile. Further clinical evaluation of its safety and efficacy is ongoing. Table 1.Summary of patient demographics25 mg(n = 1)50 mg (n = 4)100 mg (n = 3)Total (n = 8)Median age, yr6457.5 (47-63)40 (36-60)57.5 (36-64)Race, no. (%) (Asian/White/Other)1 (100%)/0/03 (75%)/0/1 (25%)2 (66.7%)/1 (33.3%)/06 (75%)/1 (12.5)/1 (12.5)Hormone-receptor status, no. (%) (Either ER or PR positive/Neither ER nor PR positive/Other)1 (100%)/0/02 (50%)/1 (25%)/1 (25%)1 (33.3%)/2 (66.7%)/04 (50%)/3 (37.5%)/1 (12.5%)ECOG score, no. (%) (0/1)0/1 (100%)1 (25%)/3 (75%)0/3 (100%)1 (12.5%)/7 (87.5%)Presence or history of brain metastases, no. (%)04 (100%)3 (100%)7 (87.5%)Previous lines of therapy, median no. (range)79 (3-14)4 (4-7)7 (3-14)Previous lines of therapy for metastatic cancer, median no. (range)67 (1-12)4 (1-4)4.5 (1-12)Previous therapies, no. (%) (Trastuzumab or Pertuzumab/T-DM1/Pyrotinib or Lapatinib/Chemotherapy)1 (100%)/0/0/1 (100%)4 (100%)/1 (25%)/3 (75%)/4 (100%)3 (100%)/0/3 (100%)/3 (100%)8 (100%)/1 (12.5%)/6 (75%)/8 (100%) Table 2.Summary of safety25 mg(n=1)50 mg (n=4)100 mg (n=3)Total (n=8)Patients with any AE, no. (%)1 (100%)3 (75%)3 (100%)7 (87.5%)Patients with any TEAE, no. (%)1 (100%)3 (75%)3 (100%)7 (87.5%)Anaemia, no. (%) (all grade/≥ Grade 3)0/02 (50%)/01 (33%)/03 (37.5%)/0Platelet count decreased, no. (%) (all grade/≥ Grade 3)0/01 (25%)/01 (33%)/02 (25%)/0Blood bilirubin increased, no. (%) (all grade/≥ Grade 3)1 (100%)/00/00/01 (12.5%)/0ALT/AST increased, no. (%) (all grade/≥ Grade 3)0/01 (25%)/00/01 (12.5%)/0Dose modification due to TEAE, no. (%) (Interruption/Reduction/Discontinuation)0/0/00/0/00/0/00/0/0 Citation Format: Jian Zhang, Nicholas McAndrew, Wenlei Yu, Xiaomei Pan, Mei Wang, Xichun Hu. Preclinical and early clinical safety and pharmacokinetics data of DZD1516, an BBB-penetrant selective HER2 inhibitor for the treatment of HER2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-43.

Abstract P4-02-08: Amcenestrant in combination with CDK4/6 inhibitor palbociclib demonstrates synergistic anti-tumor activity in ER+ endocrine-resistant breast cancer xenograft models

Abstract Nearly 70% of newly diagnosed cases of breast cancer (BC) are estrogen receptor positive (ER+) where endocrine therapy is a primary treatment. Despite initial efficacy seen with endocrine therapies, approximately 40% of patients develop acquired resistance which ultimately limits the use of these agents even as most of these tumors continue to require ERα. The strategies to combat these cancers with resistance are not yet defined and represent the next major clinical challenge in ER+ breast cancer. Amcenestrant is an optimized oral SERD (selective estrogen receptor degrader) with potent antagonist and degradation activity irrespective of ESR1 mutational status, and is currently being evaluated as monotherapy and in combination with CDK4/6 inhibitors and other targeted therapies for ER+ breast cancer patients in clinical trials. Here, we report that in preclinical models, amcenestrant achieved significant anti-tumor efficacy/regression as a monotherapy and strong synergistic activity when administered together with the CDK4/6 inhibitor, palbociclib, in subcutaneously xenografted endocrine resistant ER+ BC mouse models: ESR1-Y537S mutant-driven MCF7 tumor and HCI-013 PDX (patient-derived xenograft). Transcriptional profile analysis of xenograft tumor biopsies revealed the modulation of different pathways by SERD and palbociclib and highlighted crosstalk of ER and CDK4 signaling pathways. Interestingly, CDK4/6 inhibition by palbociclib induces partial activation of ER pathways as potential mechanism of tumor escape which is completely abolished by the combination treatment of amcenestrant with palbociclib. Early clinical data also showed that amcenestrant in combination with palbociclib, exhibited a favorable safety profile and encouraging antitumor activity in patients with endocrine resistant, ER+/HER2-, advanced breast cancer, which supports its potential to become a new endocrine backbone therapy for ER+ HER2- breast cancer. In conclusion, amcenestrant is an oral SERD, which exhibits significant anti-tumor activity as a single agent and shows synergistic activity with CDK4/6 inhibitor palbociclib in ER+ BC xenografts preclinically and in early clinical development. Citation Format: Maysoun Shomali, Zhuyan Guo, Jane Cheng, Amy Sullivan, Youssef El-Ahmad, Fangxian Sun, Sukhvinder Sidhu, Joon Sang Lee, Hui Cai, Jack Pollard, Laurent Debussche, Chris Soria, Monsif Bouaboula. Amcenestrant in combination with CDK4/6 inhibitor palbociclib demonstrates synergistic anti-tumor activity in ER+ endocrine-resistant breast cancer xenograft models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-02-08.

Abstract OT2-01-03: Trial in progress: Phase 2 study of intratumoral plasmid interleukin-12 (tavokinogene telseplasmid; TAVO™) plus electroporation in combination with pembrolizumab with or without chemotherapy in patients with inoperable locally advanced or metastatic triple-negative breast cancer (KEYNOTE-890/OMS-I141)

Abstract BACKGROUND: Interleukin-12 (IL-12) is a potent immunoregulatory cytokine that plays a key role in the crosstalk between innate (dendritic, macrophage, and natural killer) and adaptive (T and B) cells promoting anti-tumor immune responses. DNA plasmid-based IL-12 delivered to accessible tumors by intratumoral injection and electroporation (TAVO-EP) has been shown to induce activation of innate and adaptive tumor-infiltrating and peripheral immune cells, regression of treated and distant untreated lesions (abscopal effect), and expression of PD-L1 in patients with melanoma or triple-negative breast cancer (TNBC), without the systemic toxicity that has limited therapeutic use of IL-12 historically. The combination of TAVO-EP and pembrolizumab has demonstrated durable responses in melanoma patients with immunologically “cold” tumors or with prior progression on anti-PD1 therapy. Early clinical data indicate similar potential for eliciting strengthened immunogenic responses in TNBC. KEYNOTE-890 (OMS-I141) is a Phase 2 study in patients with metastatic TNBC to evaluate the safety and efficacy of TAVO-EP + pembrolizumab in the second-line or later (2L+) treatment setting (Cohort 1) or TAVO-EP + pembrolizumab + chemotherapy in the first-line (1L) setting (Cohort 2). Cohort 1 data are presented in a separate abstract. Enrollment in Cohort 2 is ongoing. METHODS: Cohort 2 of this Phase 2, open-label, multicenter study will be assessing the safety and efficacy of TAVO-EP in combination with pembrolizumab and chemotherapy as a first-line treatment for metastatic TNBC. Eligible patients are adults with metastatic TNBC (ER and PR staining &amp;lt;10%, HER2 0 to 1+ or [F]ISH-negative), no prior systemic therapy for advanced disease (neo/adjuvant therapy allowed if at least 6-month disease-free interval from last treatment), measurable disease by RECIST v1.1, at least one lesion accessible for TAVO-EP treatment, and biopsy tissue available for post-hoc central determination of PD-L1 expression. Patients will receive pembrolizumab (200 mg IV) every 3 weeks, TAVO-EP (0.5 mg/mL at dose volume of ~1/4 lesion volume) on Days 1, 5, and 8 every 6 weeks, and nab-paclitaxel (100 mg/m2 IV) on Days 1, 8, and 15 every 4 weeks. Additional chemotherapy options may be introduced in future protocol amendments. Tumor assessments will be performed every 12 weeks. On-study biopsies will be collected approximately 3 weeks after start of treatment and at disease progression. The primary endpoint will be ORR assessed by blinded independent review per RECIST v1.1. Additional endpoints will include safety and tolerability, duration of response, immune ORR, progression-free survival (PFS), immune PFS, disease control rate, and overall survival. Planned enrollment in Cohort 2 is 40 patients. Based on positive efficacy data in Cohort 1, additional cohorts are being planned and will be presented. ClinicalTrials.gov: NCT03567720 Citation Format: Melinda Telli, Bianca Devitt, Katharine Cuff, Shaveta Vinayak, Rita Nanda, Alberto J. Montero, Rina Hui, David A. Canton, Christopher Twitty, Sunny Xie, Donna Bannavong, Bridget O'Keeffe, Sandra Aung, Rohit Joshi. Trial in progress: Phase 2 study of intratumoral plasmid interleukin-12 (tavokinogene telseplasmid; TAVO™) plus electroporation in combination with pembrolizumab with or without chemotherapy in patients with inoperable locally advanced or metastatic triple-negative breast cancer (KEYNOTE-890/OMS-I141) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-01-03.

Angiogenesis as Therapeutic Target in Metastatic Prostate Cancer - Narrowing the Gap Between Bench and Bedside.

Angiogenesis in metastatic castration-resistant prostate cancer (mCRPC) has been extensively investigated as a promising druggable biological process. Nonetheless, targeting angiogenesis has failed to impact overall survival (OS) in patients with mCRPC despite promising preclinical and early clinical data. This discrepancy prompted a literature review highlighting the tumor heterogeneity and biological context of Prostate Cancer (PCa). Narrowing the gap between the bench and bedside appears critical for developing novel therapeutic strategies. Searching clinicaltrials.gov for studies examining angiogenesis inhibition in patients with PCa resulted in n=20 trials with specific angiogenesis inhibitors currently recruiting (as of September 2021). Moreover, several other compounds with known anti-angiogenic properties – such as Metformin or Curcumin – are currently investigated. In general, angiogenesis-targeting strategies in PCa include biomarker-guided treatment stratification – as well as combinatorial approaches. Beyond established angiogenesis inhibitors, PCa therapies aiming at PSMA (Prostate Specific Membrane Antigen) hold the promise to have a substantial anti-angiogenic effect – due to PSMA´s abundant expression in tumor vasculature.

The Road to CAR T-Cell Therapies for Pediatric CNS Tumors: Obstacles and New Avenues.

Pediatric central nervous system (CNS) tumors are the most common solid tumors diagnosed in children and are the leading cause of pediatric cancer-related death. Those who do survive are faced with the long-term adverse effects of the current standard of care treatments of chemotherapy, radiation, and surgery. There is a pressing need for novel therapeutic strategies to treat pediatric CNS tumors more effectively while reducing toxicity – one of these novel modalities is chimeric antigen receptor (CAR) T-cell therapy. Currently approved for use in several hematological malignancies, there are promising pre-clinical and early clinical data that suggest CAR-T cells could transform the treatment of pediatric CNS tumors. There are, however, several challenges that must be overcome to develop safe and effective CAR T-cell therapies for CNS tumors. Herein, we detail these challenges, focusing on those unique to pediatric patients including antigen selection, tumor immunogenicity and toxicity. We also discuss our perspective on future avenues for CAR T-cell therapies and potential combinatorial treatment approaches.

Gallbladder Cryoablation: Clinical and Technical Considerations

AbstractAs many as 500,000 cholecystectomies are performed per year in the United States. Frail patients are at higher risk from cholecystectomy, with reported postoperative complication and mortality rates as high as 31 and 5% in patients older than 75 years. Percutaneous cholecystostomy drainage is commonly employed in high-risk patients with cholecystitis, with over 12,000 cases performed annually. Cholecystostomy, however, is not a definitive treatment, with up to 30% of patients having a recurrent episode of cholecystitis within 4 months after tube removal. Gallbladder cryoablation has emerged as a minimally invasive procedure that achieves transmural gallbladder wall necrosis in a single session resulting in gallbladder fibrosis and involution. Early clinical data have been promising, with reported technical success of 86% and clinical success of 100% at up to 500 days of follow-up. Several challenges and unknowns remain, however, including optimal patient selection and procedural technique, the potential need for adjunct procedures to occlude the cystic duct, the implications of the immunostimulatory effects of cryoablation, and the impact of the presence of gallstones on outcomes. This article reviews the rationale behind gallbladder cryoablation, updates early clinical outcomes, and discusses the challenges that remain for the adoption of the technique for the treatment of benign gallbladder disease.

Phase I/randomized phase II trial of TRC105 plus bevacizumab versus bevacizumab in recurrent glioblastoma: North Central Cancer Treatment Group N1174 (Alliance).

BackgroundPatients with glioblastoma (GBM) have a poor prognosis and limited effective treatment options. Bevacizumab has been approved for treatment of recurrent GBM, but there is questionable survival benefit. Based on preclinical and early clinical data indicating that CD105 upregulation may represent a mechanism of resistance to bevacizumab, we hypothesized that combining bevacizumab with the anti-CD105 antibody TRC105 may improve efficacy in recurrent GBM.MethodsPhase I dose-escalation/comparative randomized phase II trial in patients with GBM. During phase I, the maximum tolerated dose (MTD) of TRC105 in combination with bevacizumab was determined. In phase II, patients were randomized 1:1 to TRC105 and bevacizumab or bevacizumab monotherapy. Patients received TRC105 (10 mg/kg) weekly and bevacizumab (10 mg/kg) every 2 weeks. Efficacy, as assessed by progression-free survival (PFS), was the primary endpoint; safety, quality of life, and correlative outcomes were also evaluated.ResultsIn total, 15 patients were enrolled in phase I and 101 in phase II; 52 patients were randomized to TRC105 with bevacizumab and 49 to bevacizumab monotherapy. The MTD was determined to be 10 mg/kg TRC105 weekly plus bevacizumab 10 mg/kg every 2 weeks. An increased occurrence of grade ≥3 adverse events was seen in the combination arm, including higher incidences of anemia. Median PFS was similar in both treatment arms: 2.9 months for combination versus 3.2 months for bevacizumab monotherapy (HR = 1.16, 95% CI = 0.75–1.78, P = .51). Quality of life scores were similar for both treatment arms.ConclusionsTRC105 in combination with bevacizumab was well tolerated in patients with recurrent GBM, but no difference in efficacy was observed compared to bevacizumab monotherapy.

Intraoperative 5-ALA fluorescence-guided resection of high-grade glioma leads to greater extent of resection with better outcomes: a systematic review.

High-grade gliomas (HGG) are the most aggressive and common malignant brain tumors in adults. They have a dismally fatal prognosis. Even if gross total resection of the enhancing tumor is achieved, inevitably, invading tumor cells that are indistinguishable to the un-aided eye are left behind, which eventually leads to tumor recurrence. 5-aminolevulinic acid (5-ALA) is an increasingly utilized intraoperative fluorescent imaging agent for patients with HGG. It enhances visualization of HGG tissue. Despite early promising randomized clinical trial data suggesting a survival benefit for 5-ALA-guided surgery, the growing body of literature must be analyzed to confirm efficacy on patient outcomes. To perform a systematic review of the literature to evaluate whether there is a beneficial effect upon survival and extent of resection due to the utilization of 5-ALA in HGG surgery. Literature regarding 5-ALA usage in HGG surgery was reviewed according to the PRISMA guidelines. Two databases, PubMed and SCOPUS, were searched for assorted combinations of the keywords "5-ALA," "high-grade glioma," "5-aminolevulinic acid," and "resection" in July 2020 for case reports and retrospective, prospective, and randomized clinical trials assessing and analyzing 5-ALA intraoperative use in patients with HGG. Entailed studies on PubMed and SCOPUS were found for screening using a snowball search technique upon the initially searched papers. Systematic reviews and meta-analyses were excluded from our PRISMA table. 3756 previously published studies were screened, 536 of which were further evaluated, and ultimately 45 were included in our systematic review. There were no date restrictions on the screened publications. Our literature search was finalized on July 16, 2020. We found an observed increase in the overall survival (OS) and progression-free survival (PFS) of the 5-ALA group compared to the white light group, as well as an observed increase in the OS and PFS of complete resections compared to incomplete resections. Of the studies that directly compared the use of 5-ALA to white light (13 of the total analyzed 45, or 28.9%), 5-ALA lead to a better PFS and OS in 88.4 and 67.5% of patients, respectively. When the studies that reported postoperative neurologic outcomes of surgeries using 5-ALA vs. white light were analyzed, 42.2% of subjects demonstrated 5-ALA use was associated with less post-op neurological deficits, whereas 34.5% demonstrated no difference between 5-ALA and without. 23.3% of studies showed that intraoperative 5-ALA guided surgeries lead to more post-op neurological deficits. Utilization of 5-ALA was found to be associated with a greater extent of resection in HGG surgeries, as well as longer OS and PFS. Postop neurologic deficit rates were mixed and inconclusive when comparing 5-ALA groups to white light groups. 5-ALA is a useful surgical adjunct for resection of HGG when patient safety is preserved.

Patritumab Deruxtecan: Paving the Way for EGFR-TKI–Resistant NSCLC

HER3 is ubiquitously expressed in EGFR-mutant non-small cell lung cancer (NSCLC) irrespective of resistant mechanisms to EGFR tyrosine kinase inhibitors, thus garnering attention as a valuable therapeutic target. In this issue of Cancer Discovery, Jänne and colleagues highlight early clinical data supporting patritumab deruxtecan as a potentially appreciable agent for previously treated EGFR-mutant NSCLC.See related article by Jänne et al., p. 74.