Second-generation Inhibitor Research Articles

CD4+/CD8+ improvement after switch from a second-generation integrase inhibitor regimen to long-acting cabotegravir and rilpivirine.

Our study assessed the CD4+/CD8+ ratio in people with HIV (PWH) switching from a second-generation integrase inhibitor regimen to long-acting cabotegravir (CAB) and rilpivirine (RPV). Over one year, we observed a significant improvement in the CD4+/CD8+ ratio; In addition, our data showed that time spent in CAB+RPV was significantly associated with an increased CD4+/CD8+ ratio. These findings suggest that long-acting therapy may enhance immune recovery, also in treatment-experienced PWH.

Abstract B011: MTA-cooperative PRMT5 inhibition (BMS-986504) induces MTAP del tumor cell-intrinsic immune evasion and regulation

Abstract Homozygous deletion of MTAP gene (MTAP del) occurs in ∼10% of all cancers. BMS- 986504 is a second-generation MTA-cooperative PRMT5 inhibitor designed to preferentially bind to the PRMT5-MTA complex which accumulates in MTAP del cancer cells and has demonstrated clinical proof-of-concept (POC) for selectively inhibiting PRMT5 activity in MTAP del patients as monotherapy. While immunotherapy (IO) has increased patient survival in many cancers and is now the standard of care in first and later lines, most patients ultimately relapse. Thus, there remains an unmet need to improve response for these patients receiving IO. BMS-986504 in combination with anti- PD1 has the potential to increase efficacy, but there is a limited understanding of the interaction between MTAP/PRMT5 biology and PD-1 blockade. Here, we evaluated the BMS-986504-induced immunological and cell killing effects on MTAP del tumor cells and T cells to understand potential mechanisms to support BMS-986504 combination opportunities with anti-PD1 therapy. Using a panel of human PBMC-derived T cells, we first demonstrate that non-activated T cells and T cells activated via anti-CD3/CD28 are insensitive to BMS-986504-induced cell killing at in vitro concentrations equivalent to clinical exposure, supporting the significantly improved selectivity margin of BMS- 986504 relative to first-generation PRMT5 inhibitors that showed T cell toxicity in vitro and on-target dose-limiting hematological toxicity in the clinic. Since previous studies have suggested that MTAP wild-type cells may be affected by MTA secreted from surrounding MTAP del tumors, we assessed T cell viability in the presence of MTA. We found that inactivated T cells maintain insensitivity to BMS-986504 treatment with or without extracellular MTA, but T cells activated via anti-CD3/CD28 are partially sensitive to BMS-986504-induced killing in the presence of MTA only. Using flow cytometry, we characterized the surface expression of immune-related markers on tumor cells treated with BMS-986504 and identified that BMS-986504 dose-dependently increases PD-L1 expression on MTAP del tumor cells, suggesting a potential immune evasion mechanism. Next, using human PBMC-derived T cell and tumor cell co-culture assays, we evaluated the ability of BMS-986504 and anti-PD1 combination to mediate both tumor-intrinsic killing and anti-tumor immune activation in MTAP del cancer cell lines. Taken together, we provide translational proof-of-concept data demonstrating that BMS- 986504 induces tumor cell-intrinsic immunological effects in MTAP del tumors, while having limited impact on T cell viability. This data supports the rationale for BMS- 986504 and IO combination, which may potentially lead to anti-tumor immune activation and improved outcome for MTAP del patients. Citation Format: Josephine Hai, Stephanie Xavier, Sangeeth George, Lars Engstrom, Pete Olson, Tyler Simpson, Ming Lei, Benjamin Chen. MTA-cooperative PRMT5 inhibition (BMS-986504) induces MTAP del tumor cell-intrinsic immune evasion and regulation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B011.

12553 Severe Hyperglycemia After Initiation Of Bictegravir Antiretroviral Therapy With Resolution Upon Discontinuation

Abstract Disclosure: S. Hudson: None. J. Aurora: None. K. Grossman: None. L. Kogelman: None. A.G. Pittas: None. Background: Antiretroviral therapy (ART) containing bictegravir (BIC), a second-generation integrase strand transfer inhibitor (INSTI), is a first-line treatment for HIV. There are mixed reports of INSTIs causing adverse metabolic effects, such as weight gain and hyperglycemia. There are cases of BIC causing hyperglycemia and diabetic ketoacidosis (DKA) within weeks to months following initiation; however, this has not been reported in clinical trials (1). It is unclear whether discontinuing BIC resolves hyperglycemia. We report a case of a patient with prediabetes who developed severe hyperglycemia after switching to a BIC-containing ART. The discontinuation of BIC resulted in significant improvement in glycemia, leading to the de-escalation of diabetes pharmacotherapy. Clinical Case: A 36-year-old woman with obesity was diagnosed with HIV during pregnancy, which was complicated by gestational diabetes mellitus. After pregnancy, she had prediabetes. Her initial ART was darunavir/cobicistat/emtricitabine/tenofovir alafenamide. Due to intolerable GI side effects, six years later, she was switched to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). Laboratory tests four months before starting BIC/FTC/TAF were consistent with prediabetes (HbA1c 6.4%, non-fasting blood glucose of 118 mg/dL). After one month, she was started on metformin when her HbA1c increased to 9.1% with a non-fasting blood glucose of 332 mg/dL. Another month later, HbA1c increased to 12.8% with a non-fasting blood glucose of 685 mg/dL without DKA. She was hospitalized for diabetes management. There were no significant changes in weight, viral load, or CD4 count. A search for secondary causes of hyperglycemia (diabetogenic medications, hypercortisolism, and autoimmune diabetes) was not revealing. She was discharged on metformin and insulin glargine. Her HIV regimen was switched to FTC/TAF and doravirine due to suspicion of BIC-induced hyperglycemia. After five months, she developed symptoms of hypoglycemia, and her estimated HbA1c by continuous glucose monitoring was 6.3%. Insulin glargine was discontinued. While on metformin, HbA1c three months later was 6.3%. Two years later on metformin and linagliptin: HbA1c was 6.1% and beta-cell function did not reveal insulin deficiency or resistance (non-fasting blood glucose 96 mg/dL, insulin 13.5 uIU/mL [RR 2.6-24.9 mIU/mL], C-peptide 3.7 ng/mL [RR 1.1-4.4 ng/mL]). Conclusion: Patients with HIV and a history of obesity and/or dysglycemia who are switched to a BIC-containing ART regimen should be educated and monitored for acute hyperglycemia. This may be due to impaired beta-cell function and/or insulin resistance; however, further research is needed to understand the mechanism. An alternative ART regimen should be considered if hyperglycemia develops. Reference: 1. Nolan NS, et al. Open Forum Infect Dis. 2021;16;8(5): ofab077. Presentation: 6/3/2024

Novel Intraprostatic MR-Guided Implantation of Multidrug-Eluting Microdevice for Testing of Systemic Therapy Agents In Situ: Proof of Concept in Intermediate-Risk and High-Risk Prostate Cancer.

The purpose of this study was to assess safety and feasibility of percutaneous MR-guided placement of an implantable microdevice (IMD) to evaluate in situ intratumor response to multiple pharmacologic agents in men with intermediate-risk and high-risk localized prostate cancer. Biocompatible IMDs measuring 750 µm in diameter and 5 mm in length were prepared with 20 reservoirs containing candidate drug and drug combinations including second-generation androgen inhibitors, PARP inhibitors, PD-1 inhibitors, and conventional chemotherapy. Men with intermediate-risk or high-risk localized prostate cancer and MRI-visible lesions were enrolled. Up to 4 IMDs were placed using a transperineal approach into MRI-visible tumors 2 days before planned radical prostatectomy. After radical prostatectomy, the IMDs and a small segment of surrounding tumor tissue were removed and sectioned, stained, and analyzed for tissue drug response by a variety of pharmacodynamic markers. Fourteen patients were enrolled: 7 (50%) with intermediate-risk and 7 (50%) with high-risk localized prostate cancer. A total of 53 IMDs were implanted (mean 3.8 per patient), and 49 IMDs (92%) were successfully retrieved. All men underwent uncomplicated robotic-assisted radical prostatectomy and bilateral pelvic lymph node dissection 2 days after IMD placement. There were no severe adverse events. Pathological examination of the tissues adjacent to the IMDs demonstrated differential drug response within patients and between patients. Limitations include small sample size. A multidrug IMD can be safely placed percutaneously into MRI-visible lesions before radical prostatectomy, enabling assessment of tumor-specific local response to multiple agents simultaneously within the tumor's normal stromal environment to guide targeted systemic therapy.

Quizartinib: a new hope in acute myeloid leukemia, an applied comprehensive review.

Acute myeloid leukemia (AML) is caused by a defective precursor leading to malignant clonal expansion, often with FMS-like tyrosine kinase-3 receptor (FLT3) mutations, particularly internal tandem duplication (ITD), which has a poor prognosis. Quizartinib, a second-generation FLT3 inhibitor, has FDA approval for relapsed/refractory AML with FLT3/ITD mutation. It has shown promise in clinical studies since 2013 due to its excellent oral absorption and potent activity on FLT3. This review explores Quizartinib's mechanism of action, efficacy in monotherapy or combination with chemotherapy, drug interactions, adverse events, resistance mechanisms and future research directions.

Toxicity Risks Associated With the Beta-Blocker Metoprolol in Marine and Freshwater Organisms: A Review.

The detection of pharmaceuticals in aquatic ecosystems has generated concern for wildlife and human health over the past several decades. β-adrenergic blocking agents are a class of drugs designed to treat cardiovascular diseases and high blood pressure. Metoprolol is a second-generation β1-adrenergic receptor inhibitor detected in effluent derived from sewage treatment plants. Our review presents an updated survey of the current state of knowledge regarding the sources, occurrence, and toxicity of metoprolol in aquatic ecosystems. We further aimed to summarize the current literature on the presence of metoprolol in various classes of aquatic species and to consider the trophic transfer of these contaminants in marine mammals. The biological impacts of metoprolol have been reported in 20 aquatic organisms, with a primary focus on cardiac function and oxidative stress. Our review reveals that concentrations of metoprolol that cause toxicity in aquatic species are above levels that are typical of marine and freshwater environments. Future studies should investigate the effects of metoprolol at lower concentrations in aquatic organisms. Other recommendations include (1) a further focus on noncardiac endpoints, because computational assessments of currently available molecular data identify gonadotropins, vitellogenin, collagen, and cytokines as potential targets of modulation, and (2) development of adverse outcome pathways for cardiac dysfunction in aquatic species to improve our understanding of molecular interactions and outcomes following exposure. As the next generation of β-blockers is developed, continued diligence is needed for assessing environmental impacts in aquatic ecosystems to determine their potential accumulation and long-term effects on wildlife and humans. Environ Toxicol Chem 2024;00:1-14. © 2024 SETAC.

Current and Future Roles of Glycoprotein IIb-IIIa Inhibitors in Primary Angioplasty for ST-Segment Elevation Myocardial Infarction.

Acute myocardial infarction still represents the major cause of mortality in high-income countries. Therefore, considerable efforts have been focused on the treatment of myocardial infarctions in the acute and long-term phase, with special attention being paid to reperfusion strategies and adjunctive antithrombotic therapies. In fact, despite the successful mechanical recanalization of the epicardial conduit, a substantial percentage of patients still experience poor myocardial reperfusion or acute/subacute in-stent thrombosis. Due the delayed onset of action of currently available oral antiplatelet therapies, glycoprotein (GP) IIb-IIIa inhibitors could be expected to improve clinical outcomes, especially when administrated in the early phase of the infarction, due to the larger platelet composition of fresh thrombi, the dynamic nature of early thrombi, and the larger amount of viable myocardium existing in the early, as compared to a delayed, phase. Considerable evidence has accumulated regarding the benefits from GP IIb-IIIa inhibitors on mortality, especially among high-risk patients and when administered as an upstream strategy. Therefore, based on currently available data, GP IIb-IIIa inhibitors can be considered when the drug can be administered within the first 3 h of symptom onset and among high-risk patients (e.g., those with advanced Killip class or an anterior myocardial infarction). Even though it is not universally accepted, in our opinion, this strategy should be implemented in a pre-hospital setting (in an ambulance) or as soon as possible when arriving at the hospital (at the Emergency Room or Coronary Care Unit, irrespective of whether they are in spoke or hub hospitals). A new, second-generation GP IIb-IIIa inhibitor (zalunfiban) appears to be highly suitable as a pre-hospital pharmacological facilitation strategy at the time of first medical contact due to its favourable features, including its simple subcutaneous administration, rapid onset of action (15 min), and limited time of action (with a half-life of ~1 h), which is likely to minimize the risk of bleeding. The ongoing CELEBRATE trial, including 2499 STEMI patients, may potentially provide compelling data to support the upstream treatment of STEMI patients undergoing mechanical reperfusion. In fact, although the current therapeutic target of increased rates of timely reperfusion has been achieved, the future goal in myocardial infarction treatment should be to achieve the most rapid reperfusion prior to primary percutaneous coronary intervention, thus further minimizing myocardial damage, or, in some cases, even preventing it completely, and improving survival.

Fatigue Management in Advanced Prostate Cancer: Real-World Insights From Qualitative Interviews With Patients

BackgroundPatients with advanced prostate cancer (PC) commonly experience fatigue related to the disease itself and its treatment, which affects their quality of life. There are limited real-world data available on patients’ experiences of fatigue while receiving PC treatment and its management. Patients and MethodsThis was a cross-sectional, noninterventional qualitative study involving individual concept-elicitation interviews with patients in the United States. Patients with advanced PC aged ≥18 years who had experienced fatigue and were on androgen-deprivation therapy in combination with second-generation androgen receptor pathway inhibitors were interviewed and their experiences quantified. ResultsOf the 143 patients screened, 13 qualified and 11 completed the interview. Most patients used the term “fatigue” (n = 8) to describe their experiences of tiredness, exhaustion, lack of energy, and weakness. Most patients (n = 8) did not receive any form of educational support from their healthcare providers (HCPs), but some expressed an interest in receiving this support (pamphlets, n = 4; discussion with HCPs, n = 4; online resources, n = 3). Most patients (n = 9) self-discovered fatigue-management strategies over the course of their disease and treatment. Patients found that rigorous exercise (n = 5), regular naps (n = 2), increased rest (n = 3), and a healthy diet (n = 3) were the most effective approaches for managing their fatigue. ConclusionTools are needed to support HCPs with counseling patients with PC for effective management of disease- and treatment-related fatigue.

Efficacy and safety of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in combination with pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC.

195 Background: While immunotherapy (IO) is established as the cornerstone of first-line treatment for KRAS-mutant NSCLC, outcomes remain suboptimal. Further progress may be achieved with the addition of targeted therapy to IO, an established first-line paradigm in some other cancer types (RCC), but historically challenging in NSCLC. Here, we study pembrolizumab plus olomorasib, a potent and highly selective second-generation inhibitor of GDP-bound KRAS G12C, in NSCLC patients treated on LOXO-RAS-20001, a phase 1/2 study of olomorasib in KRAS G12C-mutant solid tumors (NCT04956640). Methods: Patients (pts) with advanced KRAS G12C mutant NSCLC (tissue or plasma) in any treatment line, including prior KRAS G12Ci and/or prior IO were eligible. Dose escalation of olomorasib plus pembrolizumab followed a mTPI-2 method. Safety was evaluated across all pts dosed with the combination. Antitumor activity per RECIST v1.1 was studied in all pts who had ≥1 post-baseline response assessment (PBRA) or had discontinued before the first PBRA. Results: As of 30 October 2023, 50 pts with advanced NSCLC received 50-150 mg BID PO olomorasib plus 200 mg Q3W pembrolizumab. Median age was 66 yrs (range, 42-83), median number of prior systemic therapies was 2 (range, 0-8), and 34% had received a prior KRAS G12Ci. During escalation, 2 of 6 ptstreated at 150 mg BID developed grade ³3 LFTs, precluding further evaluation of this dose. In 44 pts treated at 50 or 100 mg BID, TRAEs ≥10% (related to olomorasib and/or pembrolizumab) were diarrhea (30%), ALT increased (20%), AST increased (18%), fatigue (14%), nausea (14%) and pruritus (11%); grade 3 TRAEs in ≥10% of pts were diarrhea (16%); pneumonitis was seen in 3 pts (grades 2/3/4). TRAEs led to olomorasib dose reduction in 14% of pts, olomorasib dose hold in 27%, and pembrolizumab dose hold in 18%. Due to TRAEs, 9% of pts discontinued olomorasib or pembrolizumab and 9% discontinued both. 27 pts remain on treatment, and 17 discontinued treatment (10 due to PD, 4 due to AE). Among the 30 efficacy evaluable KRAS G12Ci-naïve pts (60% IO pre-treated, 60% chemotherapy pre-treated), at a median follow-up of 6 months (95% CI, 4-7) ORR was 63% (15 PR, 4 unconfirmed PR pending/ongoing; 95% CI, 44-80) and DCR was 93% (28/30; 95% CI, 78-99); the median PFS was not estimable (95% CI, 5-NE); ORR was 75% (9/12) in PD-L1 ≥50%, 56% (10/18) in PD-L1 <50%/unknown (3 pts PD-L1 unavailable). In 9 first-line pts, ORR was 78% (6 PR, 1 unconfirmed PR pending/ongoing; 95% CI, 40-97) and DCR was 100%. Conclusions: Olomorasib (50 or 100 mg BID) in combination with pembrolizumab demonstrated favorable safety and antitumor activity in pts with KRAS G12C-mutant advanced NSCLC, supporting further development in first-line NSCLC. A global, registrational study investigating this combination in first-line NSCLC is currently enrolling (SUNRAY-01, NCT06119581). Clinical trial information: NCT04956640 .

SUNRAY-01, a pivotal, global study of olomorasib (LY3537982) in combination with pembrolizumab with or without chemotherapy for 1L treatment in KRAS G12C-mutant advanced NSCLC.

TPS218 Background: Mutations in KRAS are among the most frequent oncogenic drivers with the G12C variant found in ~13% of NSCLC. Outcomes for KRAS G12C-mutant NSCLC may be improved by combining KRAS G12C inhibitors with current 1L standard of care (SOC). Olomorasib is a potent and highly selective second-generation inhibitor of KRAS G12C, which delivers >90% sustained target occupancy in preclinical models. In the LOXO-RAS-20001 phase 1/2 study, olomorasib in combination with pembrolizumab demonstrated preliminary efficacy and a favorable safety profile.1 Methods: SUNRAY-01 (NCT06119581) is a pivotal, global, phase 3 study in 1L advanced KRAS G12C-mutated NSCLC designed to seamlessly 1) optimize the dosing of olomorasib in combination with 1L SOC, and then 2) compare efficacy and safety of olomorasib plus SOC with placebo plus SOC. In the open-label randomized dose optimization (pembrolizumab plus olomorasib 50 mg vs 100 mg BID) and single arm safety lead-in (olomorasib plus pembrolizumab, pemetrexed, platinum), the optimal dose of olomorasib for combination therapy will be determined before the phase 3 study (parts A and B) is opened for enrollment. In part A, 384 participants with PD-L1 expression ≥50% are randomized (1:1) to pembrolizumab plus olomorasib or placebo. In part B, 552 participants are randomized (1:1) to pembrolizumab, pemetrexed, platinum plus olomorasib or placebo regardless of PD-L1 expression. Allocation of participants with PD-L1 expression ≥50% to either part A or part B will be at the discretion of the investigator. The primary objective is to compare efficacy based on PFS per RECIST v1.1 by blinded independent central review. Secondary endpoints include OS, ORR, DOR, DCR, TTR, PFS2, safety and tolerability, and patient-reported outcomes. Eligible participants (≥18 years) must have a KRAS G12C mutation in tumor or blood and known PD-L1 expression (0-100%), stage IIIB, IIIC, or IV NSCLC not suitable for curative intent radical surgery or radiation therapy, measurable disease per RECIST v1.1, and an ECOG PS 0-1. Participants can be enrolled based on local KRAS and PD-L1 testing results. Participants should not have received prior systemic therapy for advanced or metastatic NSCLC, however 1 cycle of SOC treatment prior to enrollment is allowed if immediate treatment is clinically indicated. Participants with asymptomatic (lesions ≤1.5 cm) or previously treated radiographically stable brain metastases are eligible. Key exclusion criteria include history of pneumonitis/interstitial lung disease and clinically significant active cardiovascular disease or malabsorption syndrome. The study opened for enrollment in December 2023. Reference: 1. Murciano-Goroff et al. 2023 Cancer Res 83 (8 Suppl): CT028. Clinical trial information: NCT06119581 .

Adverse events in men with advanced prostate cancer treated with androgen biosynthesis inhibitors and androgen receptor inhibitors.

The use of androgen biosynthesis and second-generation androgen receptor inhibitors for advanced prostate cancer is increasing. Because these therapies alter the androgen pathway, they have been associated with cardiometabolic and neurocognitive toxicities. Although their safety profiles have been assessed in clinical trials, real-world data are limited. A 20% sample of national Medicare claims was used to perform a retrospective cohort study of Medicare beneficiaries with advanced prostate cancer treated with androgen biosynthesis (ie, abiraterone) and second-generation androgen receptor inhibitors between 2012 and 2019. Outcomes were assessed after the first fill of either class of drug for the 12-month period after starting therapy. The primary outcome was a hospital admission or emergency department visit for a cardiometabolic event. Secondary outcomes included neurocognitive events and fractures. Multivariable regression was used to assess the association between the class of drug and occurrence of an adverse event. There were 3488 (60%) men started on an androgen biosynthesis inhibitor and 2361 (40%) started on an androgen receptor inhibitor for the first time. Cardiometabolic adverse events were more common in men managed with androgen biosynthesis inhibitor (9.2% vs 7.5%, P = .027). No difference between androgen biosynthesis and androgen receptor inhibitors was observed for neurocognitive events (3.3% vs 3.4%, respectively; P = .71) or fractures (4.2% vs 3.6%, respectively; P = .26). Men with advanced prostate cancer initiating an androgen biosynthesis inhibitor for the first time more commonly had cardiometabolic events than those started on androgen receptor inhibitors. Neurocognitive events and fractures did not differ by drug class.

Effect of ABCB1 most frequent polymorphisms on the accumulation of bictegravir in recombinant HEK293 cell lines

Bictegravir, a key second-generation integrase strand transfer inhibitor in the treatment of HIV, is subject to active efflux transport mediated by ABCB1 (P-glycoprotein). Several coding variants of ABCB1 have been described and associated with variable effects on substrate drugs pharmacokinetics. Here, we investigated the effect of the four most common coding ABCB1 single nucleotide polymorphisms (i.e., c.1199G > A, c.1236C > T, c.2677G > T and c.3435C > T) on the intracellular accumulation of bictegravir. Using a previously validated HEK293 recombinant cell line model, we found decreased bictegravir intracellular concentrations in cell lines overexpressing ABCB1 as compared to control cell lines, in line with the known role of ABCB1 in bictegravir transport. However, we were unable to demonstrate any significant difference in bictegravir intracellular accumulation when comparing HEK293 cells overexpressing the wild type (1236C-2677G-3435C, 1199G) or the variant (1236C-2677G-3435T, 1236T-2677T-3435T or 1199A) proteins. These findings suggest that the ABCB1 c.1199G > A and c.1236C > T-c.2677G > T-c.3435C > T variants have no or at least limited impact on the active transport of bictegravir by ABCB1.

ALKTERNATE: A Pilot Study Alternating Lorlatinib With Crizotinib in ALK-Positive NSCLC With Prior ALK Inhibitor Resistance

IntroductionALK-positive lung cancers represent a molecularly diverse disease. With drug exposure, driving selection pressure, and resistance pathways, disease relapse will emerge. There is compelling rationale to investigate novel treatment strategies, informed by dynamic circulating tumor DNA (ctDNA) monitoring. MethodsThe single-arm, pilot study ALKTERNATE investigated fixed alternating cycles of lorlatinib intercalated with crizotinib in individuals resistant to second-generation ALK inhibitors. Dynamic ctDNA explored the correlation with disease response and disease recurrence and defined disease resistance. The primary outcome was time-to-treatment failure, a composite of tolerability, feasibility, and efficacy. Secondary outcomes included standard survival measures, toxicity, pharmacokinetic analysis, and patient-reported outcomes. Tertiary outcomes were proteogenomic analyses of tissue and plasma. ResultsA total of 15 individuals were enrolled; three encountered primary resistance to lorlatinib induction. There were 12 participants who received alternating therapy, and this approach revealed safety, feasibility, and effectiveness. Patient-reported outcomes were maintained or improved on therapy, and toxicity was consistent with previous reports. The pharmacokinetic measures were similar to the single-arm drug experience. Median time-to-treatment failure was 10 months; overall survival was 23 months. ctDNA profiles indicated inferior survival in those with preexistent TP53 mutations and those without clear or cleared ctDNA at trial induction. The study defined a vastly heterogeneous population with an abundance of ALK coexisting with non-ALK resistance variants. ConclusionsALKTERNATE revealed feasibility with a novel alternating ALK inhibitor strategy in ALK-positive NSCLC. Results support progressing inquiry into this approach and propose a flexible design with drug(s) selected and alternating time frames, informed by real-time plasma profiling. Moving this concept to treatment naive may also optimize impact.

Determination of Mefuparib in Rat Plasma and its Application to Pharmacokinetics by a Simple and Rapid UPLC-MS/MS

Background: Mefuparib (CVL218) is one of the second-generation poly-ADP-ribose polymerase (PARP) inhibitors and is used for the treatment of cancer. In this work, the levels of CVL218 in the plasma samples of rats were measured using a newly developed UPLC-MS/MS method. Methods: Six rats were given CVL218 (3 mg/kg) orally (po), and another six rats received CVL218 (1 mg/kg) intravenously (iv). Rat plasma samples were treated with acetonitrile- methanol (1:1, v/v) for protein precipitation. Cilostazol was used as the internal standard. Over the range of 0.9–450 ng/mL, a standard curve representing known concentrations of CVL218 in blank rat plasma was produced by UPLC-MS/MS. The US Food and Drug Administration (FDA) guidelines were followed in the development of the validation method. Results: In rat plasma, the accuracy ranged from 90% to 112%, and the intra-day precision and inter- day precision were both less than 15%. The recovery was higher than 87% and the matrix effect varied from 102% to 113%. In the intravenous and oral administration groups, the values of AUC(0-t) were 227.5 ±21.6 and 217.0 ±15.5 ng/mL·h, respectively, and the bioavailability was 31.8%. Furthermore, the half-life (T1/2) for oral and intravenous administration was found to be 1.6 ±0.7 h and 1.7 ±0.3 h, respectively. Conclusions: The developed UPLC-MS/MS method was successfully applied to the determination of CVL218 in rat plasma following oral and intravenous administration.

Efficacy and safety of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in combination with pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC.

8510 Background: While immunotherapy (IO) is established as the cornerstone of first-line treatment for KRAS-mutant NSCLC, outcomes remain suboptimal. Further progress may be achieved with the addition of targeted therapy to IO, an established first-line paradigm in some other cancer types (RCC), but historically challenging in NSCLC. Here, we study pembrolizumab plus olomorasib, a potent and highly selective second-generation inhibitor of GDP-bound KRAS G12C, in NSCLC patients treated on LOXO-RAS-20001, a phase 1/2 study of olomorasib in KRAS G12C-mutant solid tumors (NCT04956640). Methods: Patients (pts) with advanced KRAS G12C mutant NSCLC (tissue or plasma) in any treatment line, including prior KRAS G12Ci and/or prior IO were eligible. Dose escalation of olomorasib plus pembrolizumab followed a mTPI-2 method. Safety was evaluated across all pts dosed with the combination. Antitumor activity per RECIST v1.1 was studied in all pts who had ≥1 post-baseline response assessment (PBRA) or had discontinued before the first PBRA. Results: As of 30 October 2023, 50 pts with advanced NSCLC received 50-150 mg BID PO olomorasib plus 200 mg Q3W pembrolizumab. Median age was 66 yrs (range, 42-83), median number of prior systemic therapies was 2 (range, 0-8), and 34% had received a prior KRAS G12Ci. During escalation, 2 of 6 ptstreated at 150 mg BID developed grade ≥3 LFTs, precluding further evaluation of this dose. In 44 pts treated at 50 or 100 mg BID, TRAEs ≥10% (related to olomorasib and/or pembrolizumab) were diarrhea (30%), ALT increased (20%), AST increased (18%), fatigue (14%), nausea (14%) and pruritus (11%); grade 3 TRAEs in ≥10% of pts were diarrhea (16%); pneumonitis was seen in 3 pts (grades 2/3/4). TRAEs led to olomorasib dose reduction in 14% of pts, olomorasib dose hold in 27%, and pembrolizumab dose hold in 18%. Due to TRAEs, 9% of pts discontinued olomorasib or pembrolizumab and 9% discontinued both. 27 pts remain on treatment, and 17 discontinued treatment (10 due to PD, 4 due to AE). Among the 30 efficacy evaluable KRAS G12Ci-naïve pts (60% IO pre-treated, 60% chemotherapy pre-treated), at a median follow-up of 6 months (95% CI, 4-7) ORR was 63% (15 PR, 4 unconfirmed PR pending/ongoing; 95% CI, 44-80) and DCR was 93% (28/30; 95% CI, 78-99); the median PFS was not estimable (95% CI, 5-NE); ORR was 75% (9/12) in PD-L1 ≥50%, 56% (10/18) in PD-L1 < 50%/unknown (3 pts PD-L1 unavailable). In 9 first-line pts, ORR was 78% (6 PR, 1 unconfirmed PR pending/ongoing; 95% CI, 40-97) and DCR was 100%. Conclusions: Olomorasib (50 or 100 mg BID) in combination with pembrolizumab demonstrated favorable safety and antitumor activity in pts with KRAS G12C-mutant advanced NSCLC, supporting further development in first-line NSCLC. A global, registrational study investigating this combination in first-line NSCLC is currently enrolling (SUNRAY-01, NCT06119581). Clinical trial information: NCT04956640 .

Pan-tumor activity of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in patients with KRAS G12C-mutant advanced solid tumors.

3007 Background: Olomorasib is a potent and highly selective second-generation inhibitor of GDP-bound KRAS G12C, which preclinically delivers >90% sustained target occupancy. Here, we report updated results from LOXO-RAS-20001, a phase 1/2 study of olomorasib in patients with KRAS G12C-mutant advanced solid tumors (NCT04956640). Methods: Patients (pts) with advanced solid tumors positive for KRAS G12C (tissue or plasma) were eligible. Dose escalation used a mTPI-2 method, followed by expansion cohorts in NSCLC (with/without prior G12Ci), CRC, and other solid tumors. Safety was evaluated across all pts dosed. Antitumor activity per RECIST v1.1 was studied in all pts who had ≥1 post-baseline response assessment (PBRA) or had discontinued before the first PBRA. Serial ctDNA analysis was performed using FoundationOne Liquid CDx. Results: As of 30 October 2023, 157 pts (58 NSCLC, 32 CRC, 24 PANC, 43 other solid tumors) received single agent olomorasib (50-200 mg BID PO); 29 pts with NSCLC had received a prior KRAS G12Ci. Median age was 65 yrs (range, 36-85), median number of prior systemic therapies was 3 (range, 0-11). Any grade TRAEs were 62%; TRAEs ≥10% were diarrhea (24%), fatigue (10%), and nausea (10%); grade ≥3 TRAEs were 5%. TRAEs led to dose hold in 10% of pts, dose reduction in 3%, and discontinuation in 2%. Among 10 pts treated after discontinuing prior G12Ci due to toxicity (5/10 due to LFT increase), 1 pt (10%) required olomorasib dose reduction and none discontinued due to toxicity. 68 pts are ongoing and 89 discontinued treatment. 146 pts were efficacy evaluable (120 G12Ci-naïve; 26 with prior G12Ci) with a median follow-up of 10 months (95% CI, 7-13). As anticipated, ORR was lower in 32 pts with CRC (9%, 3 PR; DCR 84%)1 and higher in 88 pts with non-CRC tumors (40%, 30 PR and 5 uPR pending/ongoing in 13 unique tumor types; DCR 90%). mPFS ranged across tumor types from 4 months (CRC, 95% CI, 3-7) to 9 months (NSCLC, 95% CI, 3-NE). In the 26 efficacy evaluable NSCLC pts with prior KRAS G12Ci treatment (16 discontinued due to PD, 9 due to AE), the ORR was 39% (9 PR, 1 uPR pending/ongoing; DCR 73%); mPFS was 6 months (95% CI, 3-NE). In 37 pts with ctDNA results at baseline and ongoing, ctDNA response (>50% KRAS G12C VAF reduction) was seen in pts with PR (11/11), SD (17/22), and PD (1/4). Conclusions: Olomorasib demonstrates efficacy across a range of KRAS G12C-mutant solid tumors with a favorable safety profile including in pts with prior G12Ci intolerance. Activity of the second-generation G12Ci olomorasib after prior exposure to G12Ci demonstrates the increased potency and target coverage these agents can deliver compared to first generation inhibitors. Phase 2 expansion is currently enrolling pts with PANC, and a global registrational study investigating olomorasib in combination with pembrolizumab in first-line NSCLC is ongoing (NCT06119581). 1. Hollebecque A. et al. ASCO-GI 2024. Clinical trial information: NCT04956640 .

Updated study results of novel FAK/ALK/ROS1 inhibitor APG-2449 in patients (pts) with non-small-cell lung cancer (NSCLC) resistant to second-generation ALK inhibitors.

3124 Background: ALK inhibitors increase FAK pathway gene expression in ALK+ NSCLC cell lines, with the highest induced expression in drug-tolerant persister cells. This suggests that FAK pathway activation is involved in ALK inhibitor-induced early adaptive tolerance in ALK+ NSCLC. Investigational APG-2449 is a novel, orally active FAK inhibitor and a third-generation (3G) ALK/ROS1 tyrosine kinase inhibitor (TKI) with potent activity in preclinical models. APG-2449 is well tolerated at the recommended phase 2 dose (RP2D) and showed preliminary efficacy in pts resistant to 2G ALK TKIs. Here, we provide further safety and efficacy results and demonstrate associations between this therapy and FAK signaling pathways. Methods: After the RP2D was determined as 1,200 mg daily (QD), pts with NSCLC were enrolled into 2 dose expansion cohorts. Cohort 1 included pts who were resistant to 2G ALK TKIs. Cohort 2 included those who were ALK or ROS1 TKI naïve. Results: As of December 9, 2023, 144 pts (median [range] age, 53 [21-78] years; 53.5% female) with NSCLC, mesothelioma, or ovarian cancer were treated with APG-2449 at doses of 150 to 1,500 mg. A total of 129 (89.6%) pts had treatment-related adverse events (TRAEs), the most frequent of which were elevated serum creatinine (49.3%), ALT (42.4%), and AST (36.1%); nausea (28.5%); vomiting (23.6%); diarrhea (22.9%); and decreased leukocyte count (22.2%). In all, 20 (13.9%) TRAEs were grade ≥ 3. Of pts with TKI-naïve NSCLC (n = 36) treated at the RP2D, the overall response (ORR) and disease control rates (DCR = CR + PR + SD) were 68.2% (15/22) and 90.1% (20/22) in ROS1 TKI-naïve pts; and 78.6% (11/14) and 100% (14/14) in ALK TKI-naïve pts. Median progression-free survival (mPFS) in ALK TKI-naïve pts was not reached. Of 22 pts with NSCLC resistant to 2G ALK inhibitors and without targetable bypass gene mutations (e.g., KRAS G12C, BRAF V600E), 9 had PRs (9/22; 40.9%) and the mPFS during APG-2449 treatment at RP2D was 11.86 months. Nine of 12 pts in the RP2D group achieved intracranial PR, resulting in an intracranial ORR of 75.0%. Before APG-2449 administration, 17 tumor tissue samples were collected from pts with NSCLC resistant to 2G ALK inhibitors (in the RP2D group), and IHC was used to assess protein levels of phosphorylated FAK (pFAK). The PFS of pts treated with APG-2449 correlated with pFAK levels in baseline tumor tissue, and pts with higher pFAK levels were more likely to benefit from APG-2449 treatment. Conclusions: APG-2449 demonstrated preliminary efficacy in pts with NSCLC whose disease was TKI naïve and resistant to 2G ALK inhibitors, especially in brain metastases. High pFAK expression levels in baseline tumor tissue correlated with improved APG-2449 treatment responses in pts with NSCLC resistant to 2G ALK inhibitors. Internal study identifier: APG2449XC101. Clinical trial information: NCT03917043 .

SUNRAY-01, a pivotal, global study of olomorasib (LY3537982) in combination with pembrolizumab with or without chemotherapy for 1L treatment in KRAS G12C-mutant advanced NSCLC.

TPS8649 Background: Mutations in KRAS are among the most frequent oncogenic drivers with the G12C variant found in ~13% of NSCLC. Outcomes for KRAS G12C-mutant NSCLC may be improved by combining KRAS G12C inhibitors with current 1L standard of care (SOC). Olomorasib is a potent and highly selective second-generation inhibitor of KRAS G12C, which delivers >90% sustained target occupancy in preclinical models. In the LOXO-RAS-20001 phase 1/2 study, olomorasib in combination with pembrolizumab demonstrated preliminary efficacy and a favorable safety profile.1 Methods: SUNRAY-01 (NCT06119581) is a pivotal, global, phase 3 study in 1L advanced KRAS G12C-mutated NSCLC designed to seamlessly 1) optimize the dosing of olomorasib in combination with 1L SOC, and then 2) compare efficacy and safety of olomorasib plus SOC with placebo plus SOC. In the open-label randomized dose optimization (pembrolizumab plus olomorasib 50 mg vs 100 mg BID) and single arm safety lead-in (olomorasib plus pembrolizumab, pemetrexed, platinum), the optimal dose of olomorasib for combination therapy will be determined before the phase 3 study (parts A and B) is opened for enrollment. In part A, 384 participants with PD-L1 expression ≥50% are randomized (1:1) to pembrolizumab plus olomorasib or placebo. In part B, 552 participants are randomized (1:1) to pembrolizumab, pemetrexed, platinum plus olomorasib or placebo regardless of PD-L1 expression. Allocation of participants with PD-L1 expression ≥50% to either part A or part B will be at the discretion of the investigator. The primary objective is to compare efficacy based on PFS per RECIST v1.1 by blinded independent central review. Secondary endpoints include OS, ORR, DOR, DCR, TTR, PFS2, safety and tolerability, and patient-reported outcomes. Eligible participants (≥18 years) must have a KRAS G12C mutation in tumor or blood and known PD-L1 expression (0-100%), stage IIIB, IIIC, or IV NSCLC not suitable for curative intent radical surgery or radiation therapy, measurable disease per RECIST v1.1, and an ECOG PS 0-1. Participants can be enrolled based on local KRAS and PD-L1 testing results. Participants should not have received prior systemic therapy for advanced or metastatic NSCLC, however 1 cycle of SOC treatment prior to enrollment is allowed if immediate treatment is clinically indicated. Participants with asymptomatic (lesions ≤1.5 cm) or previously treated radiographically stable brain metastases are eligible. Key exclusion criteria include history of pneumonitis/interstitial lung disease and clinically significant active cardiovascular disease or malabsorption syndrome. The study opened for enrollment in December 2023. 1Murciano-Goroff et al. 2023 Cancer Res 83 (8 Suppl): CT028. Clinical trial information: NCT06119581 .

Ligand-Enabled C6-Selective C-H Arylation of Pyrrolo[2,3-d] Pyrimidine Derivatives with Pd Catalysts: An Approach to the Synthesis of EGFR Inhibitor AEE-788.

Herein, we report the Pd(II)-catalyzed direct C-H arylation of pyrrolo[2,3-d]pyrimidine derivatives with aryl iodides, which is enabled by bidentate pyridine-pyridine ligands. A range of aryl iodides proved to be suitable coupling partners affording the desired products in good yields with high levels of C6 selectivity. This protocol features good tolerance of reactive functional groups, mild reaction conditions, and a simple reaction system, which provides an expeditious route to an essential class of 6-arylpyrrolo[2,3-d]pyrimidines frequently found in bioactive compounds, and provides a step-economical access to the second-generation EGFR inhibitor AEE-788.

Weekly Afatinib in the Treatment of Advanced Non-small Cell Lung Cancer with EGFR-G719C Mutation Followed by Lobectomy: A Case Report

Introduction: Lung cancer stands as the leading cause of cancer-related deaths worldwide. Over the past three decades, the advent of tyrosine kinase inhibitors (TKIs) has marked a significant turning point in the treatment of non-small cell lung cancer (NSCLC) harboring EGFR mutations. Notably, high response rates have been observed in cases with exon 19 deletions (Del19) and Exon 21 substitution L858R mutations. Conversely, the G719X mutation on exon 18 is less prevalent, with variable sensitivity across different generations of TKIs. Afatinib, a second-generation inhibitor, gained FDA approval for the initial treatment of EGFR-mutant metastatic NSCLC in 2013, though its role remains incompletely understood within a multidisciplinary treatment framework, particularly in combination with surgery. However, the standard daily dose of 40mg Afatinib has demonstrated poor tolerability, often resulting in adverse events such as diarrhea and skin toxicity, leading to treatment discontinuation. A recent strategy involving a weekly dose of 280mg Afatinib has shown promising outcomes and a reduced risk of adverse events. Case Presentation: This case report highlights a 50 - year-old female diagnosed with stage IVa right lung adenocarcinoma metastasizing to the left lung (cT3N0M1a), revealing the rare EGFR-G719C (exon18) mutation. Following this diagnosis, the patient underwent open lobectomy. Nine months post-surgery, a treatment approach involving 280mg weekly Afatinib was initiated. Subsequently, the patient was closely monitored for 16 months with no signs of recurrence. Conclusions: EGFR G719C exhibits sensitivity to Afatinib, endorsing the use of Afatinib with fewer adverse events compared to the traditional daily dosage. Our case further advocates for collaborative strategies between medical oncologists and surgeons in the management of advanced-stage NSCLC.