Tyrosine Kinase Research Articles

Zasocitinib (TAK-279), a Selective, Oral TYK2 Inhibitor, Reduces Body Surface Area Involvement in a Phase 2b Trial in Moderate-to-Severe Plaque Psoriasis

Background: Zasocitinib (TAK-279) is an oral, allosteric, and highly selective inhibitor of tyrosine kinase 2 (TYK2). TYK2 mediates signaling from cytokines involved in the pathogenesis of psoriasis and other immune-mediated inflammatory diseases. In a phase 2b trial in patients with moderate-to-severe plaque psoriasis (NCT04999839), zasocitinib was well tolerated and demonstrated safety and efficacy, with a greater proportion of patients achieving skin clearance at doses ≥5 mg compared with placebo, with the two highest doses (15mg and 30mg) showing the strongest responses at Week 12. This analysis further evaluated the efficacy of the 15mg and 30mg doses of zasocitinib using body surface area (BSA) involvement. Methods: In this randomized, multicenter, double-blind, placebo-controlled trial, patients with moderate-to-severe plaque psoriasis were randomized 1:1:1:1:1 to receive oral zasocitinib (2, 5, 15 or 30mg) or placebo, once daily for 12 weeks. BSA outcome measures assessed at Week 12 were mean change in BSA from baseline, mean percentage change in BSA from baseline and the proportion of patients achieving a BSA threshold of ≤1% by visit. Mean change in BSA from baseline was prespecified. Results: Baseline mean (standard deviation [SD]) percentage BSA was generally consistent across the zasocitinib 15mg (n=53; 18.3 [10.3]), zasocitinib 30mg (n=52; 22.2 [14.3]) and placebo (n=52; 21.3 [13.6]) groups. Mean percentage BSA decreased as early as Week 2 and continued to decrease through to Week 12 in the zasocitinib groups, whereas scores slightly decreased in the placebo group. At Week 12, mean(SD) percentage BSA was 4.4 (5.3) (least-squares [LS] mean change: −14.7; LS mean percentage change: −72.9%) in the 15mg group, 6.5 (12.5) (LS mean change: −15.7; LS mean percentage change: −73.1%) in the 30mg group and 18.2 (13.6) (LS mean change: −4.0; LS mean percentage change: −19.3%) in the placebo group (p<0.001 for both doses versus placebo). From Week 8 onwards, higher proportions of patients achieved a BSA threshold of ≤1% in the zasocitinib 15mg and 30mg groups than in the placebo group (35.8% and 44.2% versus 0% at Week 12, respectively). Conclusion: Patients with moderate-to-severe plaque psoriasis who received the two highest doses of zasocitinib (15mg and 30mg) in the phase 2b trial achieved greater reductions in BSA than those who received placebo over 12 weeks. Further investigation of the efficacy and safety of zasocitinib in phase 3 studies in psoriasis is ongoing (NCT06088043; NCT06108544).

Deucravacitinib, an Oral Selective Tyrosine Kinase 2 (TYK2) Inhibitor, in Patients with Moderate to Severe Scalp Psoriasis: Efficacy and Safety Results of a Phase 3b/4, Multicenter, Randomized, Double-blinded, Placebo-controlled Trial (PSORIATYK SCALP)

Introduction: Deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, is approved in multiple countries for treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy. PSORIATYK SCALP, an ongoing, 52-week, phase 3b/4, multicenter, randomized, double-blinded, placebo-controlled trial, evaluated deucravacitinib efficacy/safety in patients with moderate to severe scalp psoriasis, including those with more limited overall psoriasis. Methods: Adults with moderate to severe scalp psoriasis defined by more focused and objective inclusion criteria (ss-PGA ≥3, scalp surface area involvement ≥20%, and PSSI ≥12 at baseline) and BSA involvement ≥3% were randomized 1:2 to oral placebo or deucravacitinib 6 mg once daily through Week 16. The primary efficacy outcome was ss-PGA 0/1; key secondary outcomes were PSSI 90, change from baseline in scalp-specific itch numeric rating scale (NRS), and sPGA 0/1 at Week 16. Efficacy outcomes were evaluated at Week 16 for the overall population and the subpopulation with global sPGA ≥3. Nonresponder imputation and modified baseline observation carried forward were used for patients who discontinued or had missing data for binary and continuous outcomes, respectively. Results: 154 patients were randomized (placebo, n=51; deucravacitinib, n=103). Baseline characteristics were similar in each group (placebo: mean BSA 10.0%, PASI 9.4, PSSI 32.2; deucravacitinib: mean BSA 10.5%, PASI 10.2, PSSI 33.5). In the overall population, a higher proportion of patients receiving deucravacitinib versus placebo achieved ss-PGA 0/1 at Week 16 (48.5% vs 13.7%; P<0.0001). Deucravacitinib was superior to placebo for PSSI 90 (38.8% vs 2.0%; P<0.0001) and mean change from baseline in scalp-specific itch NRS (−3.2 vs −0.7; P<0.0001). In the subpopulation (sPGA ≥3), a greater proportion achieved sPGA 0/1 with deucravacitinib versus placebo (51.0% vs 4.3%; P<0.0001). The most common adverse events (AEs) in the deucravacitinib group (≥5%) were nasopharyngitis (14.6%), upper respiratory tract infection (11.7%), acne (9.7%), headache (7.8%), COVID-19 (5.8%), and pustular acne (5.8%). Two serious AEs were reported (1/group); neither was considered treatment related or led to discontinuation. Conclusion: Deucravacitinib was efficacious and well tolerated in patients with moderate to severe scalp psoriasis, including those with less extensive overall psoriasis (BSA ≥3%). The overall psoriasis response rate (sPGA 0/1) was consistent with POETYK trial results, despite including patients with more limited BSA involvement. Safety findings were consistent with the known deucravacitinib safety profile.

Deucravacitinib, an Oral, Selective, Allosteric Tyrosine Kinase 2 (TYK2) Inhibitor, in Patients With Moderate to Severe Scalp Psoriasis: Improvement in Scalp-Related Quality of Life and Symptoms in the Phase 3b/4 Multicenter, Randomized, Double-Blinded, Placebo-Controlled PSORIATYK SCALP Trial

Introduction: PSORIATYK SCALP (NCT05478499)—an ongoing 52-week, phase 3b/4, multicenter, randomized, double-blinded, placebo-controlled trial—assesses the efficacy and safety of deucravacitinib in patients aged ≥18 years with moderate to severe scalp psoriasis (Psoriasis Scalp Severity Index ≥12, scalp-specific Physician Global Assessment ≥3, scalp surface area involvement ≥20%, and body surface area [BSA] involvement ≥3%). We assessed Week 16 patient-reported outcomes using Scalpdex, a validated, scalp-specific quality-of-life instrument, and numeric rating scales (NRSs) for scalp-specific symptoms. Methods: Patients were randomized 1:2 to placebo or deucravacitinib 6 mg for 16 weeks, stratified by previous biologic use (yes or no) and body weight (<90 or ≥90 kg). Changes from baseline in Scalpdex total score and NRS scores for scalp-specific itch, pain, and flaking were assessed with an analysis of covariance (ANCOVA) model with treatment and randomization stratification factors as fixed effects and the baseline value as a covariate. Scalpdex total score change from baseline was further assessed in BSA subgroups (BSA 3–10%, BSA >10%), using an ANCOVA model with treatment as a fixed effect and the baseline value as a covariate. P values are nominal. Results: Mean baseline scores (placebo: n=51; deucravacitinib: n=103) indicated severe impact on quality of life (Scalpdex total score >44.0) and moderate to severe symptoms (NRS ≥4.0). At Week 16, adjusted mean change from baseline (95% CI) in Scalpdex total score was greater in patients receiving deucravacitinib versus placebo (−22.3 [−26.1, −18.6] vs −10.5 [−15.7, −5.2]; P=0.0003). Changes from baseline (95% CI) in scalp-specific NRS measures were greater in patients receiving deucravacitinib versus placebo (itch: −3.2 [−3.7, −2.7] vs −0.7 [−1.4, 0.0]; pain: −2.1 [−2.6, −1.6] vs −0.1 [−0.8, 0.5]; flaking: −3.9 [−4.5, −3.4] vs −1.0 [−1.8, −0.2]; all P<0.0001). In each BSA subgroup, patients receiving deucravacitinib versus placebo reported greater Week 16 change from baseline in Scalpdex total score (BSA 3–10%: −19.8 [−23.9, −15.6] vs −10.5 [−16.1, −4.9]; P=0.0096; BSA >10%: −26.2 [−33.2, −19.3] vs −11.2 [−22.3, 0.0]; P=0.0263). Conclusion: Deucravacitinib was efficacious in improving scalp-specific psoriasis symptoms and quality of life. Furthermore, scalp-related quality of life was improved in patients receiving deucravacitinib in both BSA subgroups.

Clinical Relevance of Intensive Laboratory Monitoring With Standard Venetoclax Ramp-Up for Chronic Lymphocytic Leukemia: A Real-World Experience

PURPOSE Venetoclax is the standard of care for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) but requires intensive monitoring for optimal safety. Clinical relevance of intensive monitoring in practice is unknown, especially for patients with low or intermediate risk for tumor lysis syndrome (TLS). PATIENTS AND METHODS A retrospective review was conducted to determine clinical significance of monitoring for TLS during standard ramp-up for patients with CLL/SLL. Patients receiving abbreviated ramp-up, clinical trials, or concurrent Bruton tyrosine kinase inhibitors were excluded. The primary end point was TLS incidence, with secondary end points describing associated clinical interventions. RESULTS Fifty-five patients met study criteria. The majority of patients received venetoclax as first-line therapy (58%), with anti-CD20 antibody therapy (82%), and were at low risk of TLS (75%). No clinical TLS events occurred, whereas laboratory TLS occurred in only 1.8% of patients. No patients required antihyperuricemic therapy, and few interventions for hyperphosphatemia or hypocalcemia (3.6% of patients) were required. Additional intravenous fluids were uncommonly required (1.8% of patients), and no unplanned hospitalizations were required. CONCLUSION These findings support efforts to reduce intensive monitoring requirements during venetoclax ramp-up for patients with CLL, potentially increasing accessibility of venetoclax.

Efficacy of Deucravacitinib in Plaque Psoriasis Across a Range of Body Surface Area Involvement: Post hoc Analysis of the Randomized, Double-Blinded, Placebo-Controlled, Phase 3b/4 PSORIATYK SCALP Trial

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in the US, EU, and other countries for treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy. Scalp involvement affects approximately 80% of patients with plaque psoriasis. PSORIATYK SCALP (NCT05478499) is an ongoing, 52-week, multicenter, phase 3b/4 trial evaluating deucravacitinib in patients with moderate to severe scalp psoriasis, including those with a range of total body surface area (BSA) involvement (≥3%). These patients are candidates for systemic therapy, according to the AAD/NPF and IPC treatment guidelines. This post hoc analysis assessed efficacy in overall body psoriasis. Methods: Adults (age ≥18 years) with moderate to severe scalp psoriasis (scalp-specific Physician Global Assessment [PGA] ≥3, scalp surface area involvement ≥20%, and Psoriasis Scalp Severity Index ≥12 at baseline) and BSA involvement ≥3% were eligible for inclusion. Patients were randomized 1:2 to oral placebo (n=51) or deucravacitinib 6 mg once daily (n=103) through Week 16. Stratification factors included prior biologic use and body weight. Outcomes at Week 16 included static PGA score of 0 (clear) or 1 (almost clear) (sPGA 0/1), change from baseline in Psoriasis Area and Severity Index (PASI), and change from baseline in whole-body itch numeric rating scale (NRS). Nonresponder imputation (binary outcomes) and modified baseline observation carried forward (continuous outcomes) were used for patients with missing data. All P values are nominal. Results: Baseline characteristics were similar between groups (deucravacitinib: mean [SD], BSA 10.5% [9.6%], PASI 10.2 [6.7], whole-body itch NRS 5.8 [2.8]; placebo: mean [SD], BSA 10.0% [8.1%], PASI 9.4 [5.6], whole-body itch NRS 5.8 [2.4]). Baseline total BSA involvement was 3%-10% in most patients (deucravacitinib, 68.0%; placebo, 74.5%). At Week 16, a significantly higher proportion of patients receiving deucravacitinib versus placebo achieved sPGA 0/1 (47.6% [95% CI, 37.6%-57.6%] vs 3.9% [0.5%-13.5%], respectively; P<0.0001). Similarly, patients treated with deucravacitinib achieved greater decreases in adjusted mean change from baseline in PASI (−6.4 [95% CI, −7.3 to −5.5] vs −1.3 [−2.6 to −0.1]; P<0.0001) and whole-body itch NRS (−2.9 [−3.4 to −2.4] vs −0.4 [−1.1 to 0.3]; P<0.0001). Conclusion: In the phase 3b/4 PSORIATYK SCALP trial, deucravacitinib was efficacious in improving overall psoriasis. Efficacy was consistent with the results observed in the phase 3 POETYK PSO-1/PSO-2 trials, despite including patients with less extensive total BSA involvement.

Evaluation of Changes in Laboratory Parameters from a Phase 2b Trial of Zasocitinib (TAK-279), an Oral, Selective TYK2 Inhibitor, in Patients with Moderate-to-Severe Plaque Psoriasis

Background: Zasocitinib (TAK-279) is an oral, allosteric, and highly selective tyrosine kinase 2 inhibitor. In a recent phase 2b trial (NCT04999839), more patients with moderate-to-severe plaque psoriasis treated with zasocitinib 15 and 30 mg once daily achieved 75% improvement in the psoriasis area and severity index at Week 12 (primary endpoint) than those receiving placebo (PBO; p < 0.001). Here we report an assessment of laboratory parameters from this study. Methods: In this randomized, multicenter, double-blinded, PBO-controlled study, adults with moderate-to-severe plaque psoriasis were randomized 1:1:1:1:1 to receive oral zasocitinib (2, 5, 15 or 30 mg) or PBO once daily for 12 weeks. The safety analysis set included all patients who received ≥1 dose of the assigned study treatment. Laboratory parameters assessed throughout the trial included creatine kinase (CK), as well as hematologic (neutrophils, lymphocytes, hemoglobin, platelets), hepatic and renal (alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, estimated glomerular filtration rate), and lipid (cholesterol, triglycerides) parameters. Results: In total, 259 patients were included in the safety analysis set. Longitudinal changes in all laboratory parameters were generally similar in the PBO and zasocitinib groups. Mean values of most laboratory parameters remained within normal ranges during the study. There was no relationship between zasocitinib treatment and cytopenia. Some CK elevations were observed in both the PBO and zasocitinib groups, but most were transient or reversible and of Common Terminology Criteria for Adverse Events Grade 1 or 2 (Grade ≥2 events occurred in 2 [3.8%], 2 [4.0%], 6 [11.5%], 4 [7.5%] and 3 [5.8%] patients, in the PBO, and 2, 5, 15 and 30 mg groups, respectively), and were not associated with rhabdomyolysis. Mean triglyceride values were slightly higher than normal ranges at baseline and Week 12 in all treatment groups, including PBO, and were mainly asymptomatic, mild-to-moderate elevations. These changes were not accompanied by increases in serum cholesterol levels. Conclusion: Zasocitinib treatment did not result in adverse changes in hematologic, hepatic, renal or lipid parameters that are associated with Janus kinase (JAK) inhibition, suggesting that the mechanism of action of zasocitinib is distinct from that of JAK1/2/3 inhibition. Further phase 3 studies of zasocitinib in psoriasis are ongoing to confirm these observations (NCT06088043; NCT06108544).

Deucravacitinib in Plaque Psoriasis: Laboratory Parameters Through 4 Years of Treatment in the Phase 3 POETYK PSO-1, PSO-2, and LTE Trials

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in multiple countries for treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy. Deucravacitinib was efficacious versus placebo and apremilast and was well tolerated in the global, 52-week, phase 3 POETYK PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751) parent trials. At Week 52, patients could enroll in the ongoing POETYK long-term extension (LTE) (NCT04036435) trial and receive open-label deucravacitinib. Changes in blood laboratory parameters known to be associated with Janus kinase (JAK) 1,2,3 inhibitors were evaluated through 4 years of deucravacitinib treatment. Methods: Changes from baseline in lipid (cholesterol, triglycerides), chemistry (alanine aminotransferase [ALT], aspartate aminotransferase [AST], creatinine, creatine phosphokinase [CPK]), and hematology (hemoglobin, lymphocytes, neutrophils, platelets) parameters in the blood known to be affected by JAK1,2,3 inhibitors in clinical trials were evaluated through Week 208 (4 years; data cutoff, November 1, 2023). Treatment discontinuations due to laboratory abnormalities were assessed. Results: A total of 1519 patients received ≥1 deucravacitinib dose (total exposure, 4392.8 person-years); 1203 (79.2%) had ≥52 weeks and 542 (35.7%) had ≥208 weeks of continuous deucravacitinib exposure (median, 185 weeks). No trends or clinically meaningful mean changes from baseline were observed in any of the above laboratory parameters. In total, 3 patients discontinued treatment due to increased CPK, and 1 patient each discontinued due to lymphopenia, abnormal hepatic function, increased ALT, and increased AST. Discontinuations due to triglyceride elevations were not observed. Conclusion: In PSO-1/PSO-2/LTE, no trends or clinically meaningful mean changes from baseline were observed in lipid, chemistry, or hematology parameters, in contrast to signature changes (eg, increased cholesterol, creatinine, serum transaminases, CPK, cytopenias) observed with JAK1,2,3 inhibitors. Discontinuations due to laboratory abnormalities noted above were rare (n=7 events) through 4 years of deucravacitinib treatment. Results suggest deucravacitinib treatment does not warrant routine laboratory testing for all patients, in contrast with the requirements for JAK1,2,3 inhibitors, reflecting its selectivity for TYK2.

Deucravacitinib in Moderate to Severe Plaque Psoriasis: Comorbidities and Use of Prior and Concomitant Medication in Patients Enrolled in the Phase 3 POETYK PSO-1 and PSO-2 Trials

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in the US, EU, and other countries for treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy. Deucravacitinib was superior to placebo and apremilast in two global, phase 3 trials, POETYK PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751), in moderate to severe plaque psoriasis. Here, we evaluate the comorbidities present at baseline and use of prior and concomitant medications in the pooled POETYK PSO-1 and PSO-2 trial populations to more comprehensively describe the medical history of individuals who participated in the deucravacitinib phase 3 trials. Methods: In POETYK PSO-1 and PSO-2, adults with moderate to severe plaque psoriasis were randomized 1:2:1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily. The rates of baseline comorbidities and medications received before and concomitantly with deucravacitinib in the pooled POETYK PSO trials were assessed. Medication classes evaluated included antidiabetic, antihypertensive and cardiovascular, lipid-reducing, anti-anxiety/depression, and oral contraceptive therapies. Results: Baseline patient demographics were similar across treatment arms. Metabolism and nutrition disorders were reported most often in each treatment arm (placebo, 42.7%; deucravacitinib, 39.2%; apremilast, 38.4%), followed by vascular disorders (33.7%, 34.9%, and 31.8%, respectively). Hypertension was the most common baseline medical condition (placebo, 30.3%, deucravacitinib, 32.8%, and apremilast, 29.1%), with obesity, hyperlipidemia, type 2 diabetes mellitus, and seasonal allergies each reported in 10% to 12% of patients in at least one treatment arm. Antihypertensive and cardiovascular agents, lipid-reducing agents, and antidiabetic agents were the most commonly reported medications. Conclusion: The phase 3 POETYK PSO trials enrolled adults with moderate to severe plaque psoriasis with a range of comorbidities consistent with the real-world population of patients with psoriasis. Medication classes used by patients were consistent with the comorbidities reported at baseline in both trials.

Abstract A040: A novel stroma-mediated positive interaction between resistant and sensitive cells in non-small cell lung cancer facilitates drug resistance

Abstract Resistance to targeted therapies, particularly those inhibiting oncogenic tyrosine kinases (TKIs), presents a significant challenge in the treatment of advanced non-small cell lung cancer (NSCLC). Despite initial robust clinical responses, tumors often relapse due to the emergence of resistant cell populations. The origins of this resistance—whether it is pre-existing in a subset of tumor cells or arises de novo during treatment—remains a critical question in understanding and combating therapeutic failure. To investigate this, we developed in silico mathematical models that integrate both pre-existing and de novo resistance mechanisms within a framework that explicitly integrates the stromal niche. Our study focused on the evolutionary dynamics of NSCLC in response to therapy, using a hybrid agent-based spatial modeling framework (HAL) to simulate tumor behavior under treatment. These models were designed to simulate the complex interactions between resistant and sensitive tumor cells, mediated by the stroma, and to predict the timing of relapse based on these interactions. Our findings suggest that stroma-mediated interactions play a crucial role in the evolutionary dynamics of therapy responses, influencing the fitness and survival of both resistant and sensitive cells. Specifically, our models predict that pre-existing resistance is unlikely to be compatible with the long remission periods observed in a substantial subset of patients treated with advanced anaplastic lymphoma kinase (ALK) inhibitors. This conclusion was supported by the observed relapse times and volumetric tumor growth data from subsequent animal models. Moreover, our analyses highlight the importance of ecological factors within the tumor microenvironment in shaping the response to therapy. The spatial models we developed reveal that the stroma can foster positive interactions between resistant and sensitive cells, thereby accelerating the emergence of resistance. These insights underscore the need to consider the stromal niche when developing new therapeutic strategies and when interpreting the dynamics of drug resistance. In conclusion, our study provides new insights into the role of stroma in mediating resistance to TKIs in NSCLC. By combining mathematical modeling with experimental data, we have elucidated how stroma-mediated interactions between tumor cells can influence the evolution of resistance, challenging the assumption that pre-existing resistance alone drives relapses in TKI-treated patients. Our findings emphasize the need for adaptive therapeutic approaches that anticipate and disrupt these microenvironmental interactions to improve patient outcomes. Citation Format: Rishi M. Shah, Sagnik Yarlagadda, Mark Robertson-Tessi, Bina Desai, Tatiana Miti, Daria Miroshnychenko, David Basanta, Andriy Marusyk, Alexander Anderson. A novel stroma-mediated positive interaction between resistant and sensitive cells in non-small cell lung cancer facilitates drug resistance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A040.

Abstract C029: PM2.5-induced drug resistance in lung cancer

Abstract Long-term exposure to PM2.5 air pollution is a significant contributor to lung cancer incidence. Our previous studies have shown that such exposure promotes lung cancer progression by activating the EGFR (epidermal growth factor receptor) and AhR (aryl hydrocarbon Receptor) pathways. We observed that in lung cancer cells with EGFR mutations, prolonged PM2.5 exposure induces EGFR activation, resulting in accelerated tumor cell growth both in vitro and in vivo. This suggests that PM2.5 may play a role in the resistance to EGFR-TKI (tyrosine kinase inhibitor) therapies, raising concerns about treatment efficacy. To explore this, we exposed the EGFR-mutant lung cancer cell line to PM2.5 for 90 days. Our results revealed that long-term exposure not only reduced the therapeutic effect of EGFR-TKIs but also increased the expression of cMyc, a gene linked to poor prognosis and drug resistance. We further confirmed that PM2.5-induced EGFR-TKI resistance is driven by the AhR-cMyc pathway. AhR, activated by environmental toxins in PM2.5, increases cMyc expression, leading to drug resistance. When we administered cMyc inhibitors, the PM2.5-exposed cells regained sensitivity to EGFR-TKI therapy. These findings indicate that targeting the AhR-cMyc pathway could be a promising approach to overcome PM2.5-induced resistance in lung cancer treatment. Further research is needed to explore the broader implications of environmental pollution on cancer therapy and to develop strategies to counteract the effects of pollutants like PM2.5. Citation Format: Chi-Yuan Chen, Chieh-Wen Chan, Tong-Hong Wang. PM2.5-induced drug resistance in lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C029.

Therapeutic advances in the targeting of ROR1 in hematological cancers

AbstractReceptor tyrosine kinases (RTKs) are key cell surface receptors involved in cell communication and signal transduction, with great importance in cell growth, differentiation, survival, and metabolism. Dysregulation of RTKs, such as EGFR, VEGFR, HER2 or ROR, could lead to various diseases, particularly cancers. ROR1 has emerged as a promising target in hematological malignancies. The development of ROR1 targeted therapies is continuously growing leading to remarkable novel therapeutical approaches using mAbs, antibody-drug conjugates, several small molecules or CAR T cells which have shown encouraging preclinical results. In the hematological field, mAbs, small molecules, BiTEs or CAR T cell therapies displayed promising outcomes with the clinical trials data encouraging the use of anti-ROR1 therapies. This paper aims to offer a comprehensive analysis of the current landscape of ROR1-targeted therapies in hematological malignancies marking the innovative approaches with promising preclinical and clinical. Offering a better understanding of structural and functional aspects of ROR1 could lead to new perspectives in targeting a wide spectrum of malignancies.

Abstract B046: Pyk2 and MEK/ERK signaling regulate the extracellular vesicle release and tumor-associated myeloid Cells in glioblastoma

Abstract Glioblastoma (GBM) is often fatal within a year despite treatment, with immune checkpoint blockade therapies benefiting only about 10% of patients. Non-responsive GBMs exhibit an immunosuppressive profile and higher levels of tumor-associated myeloid cells (TAMs). Addressing this immunosuppressive microenvironment is a major challenge in GBM immunotherapy. Our recent studies have identified a positive correlation between Proline-Rich Tyrosine Kinase 2 (Pyk2) activation in GBM tumor cells and the cytokine expression profile of TAMs. This identified Pyk2 as a potential prognostic marker for the immune state in GBM tumor microenvironment. We hypothesize that Pyk2 and MEK/Erk signaling in GBM cells regulate the release of chemokines and cytokines through extracellular vesicles (EVs) by modulating the actin cytoskeleton, thereby impacting TAM activation. The study aimed to investigate the role of Pyk2/MEK/Erk signaling in EV release in GBM cells, potentially revealing new therapeutic targets. Two humans primary GBM cell lines, with and without Pyk2 CRISPR/Cas9 knockout (Pyk2KO), were used. Flow cytometric analysis of EVs, enriched from cell-conditioned medium, identified a shift towards larger in diameter EVs populations in Pyk2 KO cells, compared to wild-type (WT) cells. Analysis using Integrin as a plasma membrane marker showed that 84.70% of Integrin+ and 15.30% of Integrin- EVs were derived from WT cells, whereas Pyk2KO cells produced 89.07% Integrin+ and 10.93% Integrin- EVs. Treatment of WT cells with the Erk/MEK inhibitor Avutometinib (1µM) altered the EV population’s ratio to 79.11% Integrin+ and 20.89% Integrin-. Similarly, Avutometinib treatment of Pyk2KO cells resulted in 78.83% Integrin+ and 21.17% Integrin- EVs, similar to the ratio observed in Avutometinib-treated WT cells. Western blot and PCR analysis of EVs content revealed a significant reduction in CCL2, CCL5, tumor necrosis factor (TNF), and vascular endothelial growth factors (VEGF) in EVs from Pyk2KO GBM cells, compared to WT. In vivo studies using GL261/C57Bl/6 mouse glioma implantation model and flow cytometric analysis of TAMs from tumors generated with WT and Pyk2KO GL261 cells demonstrated increased infiltration of TNF+/IFNg+ CD8+ lymphocytes and Ly6C+/CD206- myeloid cells, alongside a reduction in CD45+/CD11b+/CD33+/MHCII- myeloid-derived suppressor cells. PCR analysis of TAM isolated from Pyk2KO tumors revealed lower gene expression of TNF, CCL5, CCL2, VEGFa, and epidermal growth factor (EGF) compared to WT tumors. The study highlights that Pyk2/MEK/Erk signaling regulates the immune microenvironment in GBM by influencing EV release, which impacts TAM cell activation. Pyk2 primarily regulates the release of Integrin- EVs, while MEK/Erk predominantly regulates EVs shed from the plasma membrane. The findings underscore the interplay between Pyk2 and MEK/Erk signaling in regulating EV biogenesis and composition. Citation Format: Neisha M. Ramirez. Pyk2 and MEK/ERK signaling regulate the extracellular vesicle release and tumor-associated myeloid Cells in glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B046.

Abstract A036: DDR2 in ovarian tumor CAFs controls ferroptosis and response to Olaparib

Abstract In ovarian cancer, resistance to conventional cancer treatments has stimulated finding alternative targets that induce tumor cell death. Ferroptosis, a lipid peroxide-triggered form of iron-dependent cell death, is one such pathway. Current research has focused primarily on tumor cell-intrinsic mechanisms or how tumor associated immune cells might impact tumor cell ferroptosis. Cancer-associated fibroblasts (CAFs) are other key stromal cells in the tumor microenvironment and play critical roles in cancer progression, metastasis, and chemotherapeutic response. In ovarian cancer, the collagen receptor tyrosine kinase DDR2 is predominantly expressed by tumor stromal CAFs, not immune cell, and high tumor stromal cell expression of DDR2 in ovarian tumors is associated with poor survival and resistance to therapy. Thus, we asked whether DDR2 could impact ferroptosis regulation in CAFs, and if so, how this effect of DDR2 could impact ovarian tumor cell responses to cytocidal therapies. Through various genetic means, we generated multiple DDR2-expressing and DDR2-deficient human ovarian tumor and mouse breast tumor CAFs. We evaluated the response of the various CAFs to ferroptosis inducers (Erastin and RSL3) and inhibitors (Ferrostatin-1 and Deferoxamine). We find that the presence of DDR2 in CAFs protects these cells from induced ferroptosis through regulation of the xCT- GSH-GPX4 antioxidant pathway and cellular iron metabolism. DDR2-dependent regulation of xCT-GSH-GPX4 occurs through non-canonical activation of NRF2 via the Sequestosome-1 (SQSTM1/p62) protein. In iron metabolism, DDR2 affects the labile iron pool (LIP) by regulating ferritinophagy. The actions of DDR2 in CAFs protects these cells against Olaparib therapy, by inhibiting Olaparib-induced ferroptosis. Ovarian tumor CAF culture supernatant was found to protect ovarian tumor cell response to Erastin-induced ferroptosis, in a DDR2- dependent manner. Overall, this study uncovered a novel function of the action of DDR2 in tumor stromal CAFs in controlling iron and the xCT-GSH-GPX4 ferroptosis regulatory axis through non-canonical p62-KEAP1-NRF2 activation. These findings suggest that CAFs, through DDR2-mediated regulation of ferroptosis, could play a role in therapeutic sensitivity/resistance in ovarian cancer. Citation Format: Julien Lesage, Alessandra DiMauro, Katherine C. Fuh, Gregory D. Longmore. DDR2 in ovarian tumor CAFs controls ferroptosis and response to Olaparib [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A036.

Abstract A003: The role of aging in promoting immune mediated reactivation from metastatic melanoma dormancy

Abstract Metastasis is the primary cause of melanoma death. A major problem with the vast majority of previous studies is that young mice (8-weeks old, equivalent to 20 human years) are used to investigate the mechanisms of metastatic outgrowth, whereas the median age of melanoma diagnosis in humans is ∼65 years. Advanced age also correlates with metastasis, mortality, and immune dysfunction. Moreover, most studies often only focus on lung metastases, despite melanoma commonly metastasizing to sites such as the liver in patients, which are significantly more resistant to checkpoint inhibitors (ICIs) compared to patients with lung metastases. We have begun addressing these core limitations by developing novel syngeneic mouse models of melanoma metastasis and colonization in young (8-week), middle-aged (12-month), and geriatric (18-22 month) mice, in which metastatic colonization/dissemination can be targeted to either the lung or liver alone, or to both simultaneously. Our data now show that aging promotes reactivation of dormant tumor cells and subsequent outgrowth of lung and liver metastases. We have found that frontline innate lymphocytes such as NK-cells and γδ T-cells are decreased in the pre-metastatic lung and livers of aged mice relative to young mice and remain decreased during early and late-stage metastasis. Using inducible KO mouse models and antibody depletion methods in young growth restrictive mice, we find that depletion of either NK-cells or γδ T-cells is sufficient to promote reactivation from dormancy and resistance to anti-PD1 therapy. Secondly, we further delineated changes in the post-metastatic lung and liver niche. We find that PROS1 secretion by reactivated melanoma cells expressing high levels of the MER tyrosine kinase receptor (MER) in the aged metastatic lung and liver increases CD11b myeloid cells expressing the immunosuppressive factor ARG1. Within this CD11b subset, we see an increase in polymorphonuclear myeloid derived suppressor cells (PMN MDSCs). Treatment with recombinant ARG1 promotes reactivation from dormancy in young mice whilst depletion of PMN MDSCs inhibits age induced outgrowth in the lung and liver. Overall, our study highlights common immune-mediated age-related changes in the pre and post metastatic lung and liver which contribute to aggressive metastatic initiation, reactivation from dormancy, progression, and resistance to anti-PD1 Citation Format: Kelly Coutant, Jhon Passamonte, Christopher Price, Pulkit Datt, Mitchell Fane. The role of aging in promoting immune mediated reactivation from metastatic melanoma dormancy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A003.

Abstract C039: The impact of antiangiogenic therapy on blood vessels and CD8 infiltration in renal cancer metastases is space, time, site, dose, and drug dependent

Abstract Clear cell renal cell carcinoma (ccRCC) is the most prevalent renal neoplasm, with bone as a major site for distant spread in 35% to 40% of the patients. These metastases are typically osteolytic, resistant to treatments, hence result in a variety of skeletal-related complications strongly contributing to mortality. A key feature of ccRCC is the loss of function of the von Hippel–Lindau (VHL) protein leading to extensive angiogenesis. Consequently, different anti-angiogenic tyrosine kinase inhibitors (TKIs) are used as the first or subsequent line of treatment for these patients as single agents or in combination with immune checkpoint inhibitors. However, limited data about their efficacy in bone metastasis is available, and their impact on the immune infiltrate, including effector CD8 cells, is unclear. We hypothesized that TKIs, by inhibiting angiogenesis, significantly reprogram the microenvironment and limit immune infiltration in space, time, dose, and drug dependent fashion. To test these hypotheses, we developed an immunocompetent mouse model of bone metastasis by orthotopical intratibial implantation of luciferase-GFP-positive mouse RENCA-VHL- cell line. Interestingly, intratibial injections gave rise to metastases in lungs, creating a unique opportunity to study two metastatic sites. Three different TKIs currently used in patients were tested and compared to control: axitinib (A), cabozantinib (C), and lenvantinib (L). Outcomes were monitored by macroscopic bioluminescence detection in vivo, 3D multiparametric spatial analysis of bones and lungs, in vivo, and ex vivo. Compared to control-treated mice, high doses of A, C, and L significantly reduced tumor progression in both tumor sites. Even though these TKIs are clinically considered equal, significant differences in their efficacy were noted. Spatial analysis of tumor cells and blood vessels showed a significant decrease in blood vessels formation in both an organ- and TKI-specific pattern over time. Additionally, the reduction of neo angiogenesis in treated tumors directly limited the infiltration of CD8 cells, which localized at the interface with tumor free bone/lung tissue. Interestingly, TKI dose reduction significantly improved CD8 infiltration, while controlling tumor size. TKI withdrawal, instead, led to rapid progression of tumor in both sites and significantly shortened mice survival. In conclusion, we established bone and lung metastatic models of ccRCC and characterized and compared the effects of three antiangiogenic TKIs on angiogenesis and CD8 infiltration. TKIs reduced tumor growth and progression, because of blood vessel formation inhibition. Furthermore, TKI treatment reduced the infiltration of effector T cells in tumors in a dose-dependent manner, an outcome that can have a major impact when TKIs are combined with immunotherapy, a preferential therapeutic regimen for ccRCC patients. Overall, we believe our studies provide important insights and efficacy predictions for innovative therapeutic applications in ccRCC bone metastatic patients. Citation Format: Stefan Maksimovic, Nina Costanza Boscolo, Ludovica La Posta, Matthew T. Campbell, Eleonora Dondossola. The impact of antiangiogenic therapy on blood vessels and CD8 infiltration in renal cancer metastases is space, time, site, dose, and drug dependent [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C039.

Advanced lung adenocarcinoma with EGFR 19-del mutation transforms into squamous cell carcinoma after EGFR tyrosine kinase inhibitor treatment

In this editorial we comment on the article by Ji et al . We focus specifically on the EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment and the development of drug resistance to EGFR-TKIs.

A prophylactic tyrosine kinase inhibitor strategy based on measurable residual disease pre-transplantation for Ph+ acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation: A prospective multicenter cohort study.

Relapse is the major cause of treatment failure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed to evaluate the effect of a prophylactic tyrosine kinase inhibitor (TKI) strategy on relapse in this population. Patients were assigned to prophylactic or control groups based on measurable residual disease (MRD) pre-transplantation. The primary endpoint was the cumulative incidence of relapse. A total of 110 patients with Ph+ ALL undergoing allo-HSCT were enrolled in this prospective study. Thirty-eight patients with positive MRD pre-transplantation were included in the prophylactic group, and 72 with negative MRD pre-transplantation were included in the control group. The 4-year cumulative incidence of relapse was 25.3% (95% CI: 12.1%-41.0%) and 20.3% (11.6%-30.7%; HR = 1.272, 95% CI: 0.551-2.940, p = .549), and non-relapse mortality was 10.5% (3.3%-22.7%) and 9.7% (4.2%-17.9%; HR = 1.094, 95% CI: 0.320-3.738, p = .928) in the prophylactic and control groups. The 4-year overall survival was 71.8% (53.2%-84.1%) and 84.1% (72.9%-90.9%; HR = 1.746, 95% CI: 0.741-4.112, p = .196), and leukemia-free survival was 64.1% (45.8%-77.7%) and 70.0% (57.6%-79.4%; HR = 1.212, 95% CI: 0.607-2.421, p = .585) in the prophylactic and control groups. Our results suggest that prophylactic TKI post-HSCT in patients with positive MRD pre-transplantation can produce outcomes comparable to negative MRD pre-transplantation without TKI post-HSCT.

Promising PD-1 antagonists for liver cancer: an evaluation of phase II and III results.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a significant cause of cancer-related morbidity and mortality. Limited treatment options for advanced stages emphasize the need for effective therapies. This review examines immune checkpoint inhibitors (ICIs), specifically PD-1, PD-L1, and CTLA-4 inhibitors, as novel treatments for advanced HCC. The review includes data from phase II and III clinical trials that evaluate ICI combinations with tyrosine kinase inhibitors (TKIs) and anti-angiogenic agents, as well as locoregional treatments such as Transarterial Chemoembolization (TACE). Clinical outcomes, including progression-free survival and overall response rates, were analyzed along with the incidence and management of immune-related adverse events (irAEs). A systematic literature review method was applied to ensure the inclusion of comprehensive, high-quality studies. ICI-based therapies and their combinations are reshaping the treatment landscape for advanced HCC by providing improved outcomes and potentially extending patient survival. Although promising, these therapies require further refinement to optimize sequencing and treatment selection, especially for patients with different levels of liver function and disease stages. Managing adverse effects effectively is essential for maximizing the benefits of these therapies in clinical practice. Continued research is needed to support the development of personalized approaches that can better tailor these treatments to individual patient needs, ultimately enhancing the overall effectiveness and safety of HCC management.

Nintedanib attenuates NLRP3 inflammasome-driven liver fibrosis by targeting Src signaling.

Liver injury induces an inflammatory response that activates hepatic stellate cells, which is the initial factor of liver fibrosis. Nintedanib, a multi-targeted tyrosine kinase inhibitor targeting the Src signalling pathway, has been approved for the treatment of idiopathic pulmonary fibrosis. However, it is still not known whether nintedanib ameliorates liver fibrosis by inhibiting inflammasome activation. Here, a carbon tetrachloride (CCl4)-induced liver fibrosis model was used to assess the anti-fibrotic efficacy of nintedanib in vivo. Lipopolysaccharide and ATP were used to activate nucleotide oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in LX-2 cells, and the efficacy of nintedanib on NLRP3 inflammasome activation was evaluated. Moreover, we used Src-overexpressing and Src-downregulating lentiviruses to transfect LX-2 cells to explore the targets of nintedanib. Nintedanib attenuated inflammation and extracellular matrix accumulation in CCl4-induced fibrotic livers and reduced the expression of NLRP3, fibrotic makers, and the phosphorylation of Src, epidermal growth factor receptor (EGFR), AKT, ERK1/2 in LX-2 cells. Furthermore, nintedanib thwarted NLRP3 inflammasome activation by suppressing the phosphorylation of Src and its downstream signalling pathway and reducing reactive oxygen species production. Our study indicates that nintedanib effectively suppresses NLRP3 inflammasome activation and has the potential for the treatment of liver fibrosis.

Contemporary treatment of metastatic clear cell renal cell carcinoma

Renal cell carcinoma is one of the mostcommon malignant tumors in Germany with an increasing incidence. Drug therapy is indicated in relapsed or metastatic disease. The article is based on the content of the recent guidelines and aselective literature search. Combination therapies based on acheckpoint inhibitor are the current standard in first-line treatment of metastatic renal cell carcinoma. The median overall survival could thus be extended to > 50months. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score is used for risk classification. When selecting asuitable combination therapy, it is important to consider the advantages and disadvantages for each individual patient. There is currently no standard for follow-up therapies. So far, combination therapies have not shown any significant advantage in second-line treatment. It is recommended to switch to asubstance that has not yet been used. Currently, one purely immuno-oncology combination and four combinations of one immune checkpoint inhibitor and one tyrosine kinase inhibitor (TKI) are approved for first-line therapy in Germany. The added value of further intensification of therapy, in particular through triple combinations or further combination therapy in the second line, has not yet been proven.