IC Regimen: Delaying Resistance to Lorlatinib in ALK Driven Cancers by Adding Repurposed Itraconazole and Cilostazol.

Lorlatinib is a pharmaceutical ALK kinase inhibitor used to treat ALK driven non-small cell lung cancers. This paper analyses the intersection of past published data on the physiological consequences of two unrelated drugs from general medical practice-itraconazole and cilostazol-with the pathophysiology of ALK positive non-small cell lung cancer. A conclusion from that data analysis is that adding itraconazole and cilostazol may make lorlatinib more effective. Itraconazole, although marketed worldwide as a generic antifungal drug, also inhibits Hedgehog signaling, Wnt signaling, hepatic CYP3A4, and the p-gp efflux pump. Cilostazol, marketed worldwide as a generic thrombosis preventative drug, acts by inhibiting phosphodiesterase 3, and, by so doing, lowers platelets' adhesion, thereby partially depriving malignant cells of the many tumor trophic growth factors supplied by platelets. Itraconazole may enhance lorlatinib effectiveness by (i) reducing or stopping a Hedgehog-ALK amplifying feedback loop, by (ii) increasing lorlatinib's brain levels by p-gp inhibition, and by (iii) inhibiting growth drive from Wnt signaling. Cilostazol, surprisingly, carries minimal bleeding risk, lower than that of aspirin. Risk/benefit assessment of the combination of metastatic ALK positive lung cancer being a low-survival disease with the predicted safety of itraconazole-cilostazol augmentation of lorlatinib favors a trial of this drug trio in ALK positive lung cancer.

Real-World Treatment Patterns and Outcomes Across Three Lines of Therapy in Patients with ALK+ NSCLC.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard first- and second-line treatment for advanced ALK+ non-small cell lung cancer (NSCLC). We evaluated outcomes in patients with ALK+ NSCLC receiving third-line ALK TKI versus non-ALK-directed therapy. METHODS: Flatiron Health OncoEMR data were extracted for patients with ALK+ NSCLC initiating first-line ALK TKI between January 2015 and March 2022 followed by second-line ALK TKI and third-line ALK TKI (group A) or non-TKI therapy (group B). Time-to-treatment discontinuation (TTD) and overall survival (OS) were analyzed using multivariate modelling. RESULTS: Among patients receiving third-line ALK TKI (A, n = 85) or non-TKI therapy (B, n = 43), most received first-line crizotinib (A/B: 64%/60%) and second-line alectinib (36%/30%), ceritinib (24%/19%), or lorlatinib (15%/30%). Common third-line treatments were lorlatinib/alectinib (41%/33%) in A and immunotherapy, chemotherapy, or chemotherapy + immunotherapy (30%/28%/21%) in B. Group A versus B had longer TTD of first-line treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.41-0.93; p = 0.020) and second-line treatment (HR 0.50, 95% CI 0.33-0.75; p < 0.001) and longer OS from start of first-line treatment (HR 0.32, 95% CI 0.19-0.54; p < 0.001) and second-line treatment (HR 0.40, 95% CI 0.24-0.66; p < 0.001). For third-line treatment, median TTD (A/B) was 6.2/2.4 months (HR 0.61, 95% CI 0.37-1.00; p = 0.049) and OS was 17.6/6.5 months (HR 0.57, 95% CI 0.33-0.98; p = 0.042). CONCLUSIONS: Patients receiving third-line non-ALK-directed therapy had suboptimal outcomes on prior TKIs. Patients with longer duration of prior ALK TKI treatment appeared to benefit from third-line ALK TKIs.

Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient.

Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

Dissecting the role of ALK double mutations in drug resistance to lorlatinib with in-depth theoretical modeling and analysis.

Anaplastic lymphoma kinase (ALK) is implicated in the genesis of multiple malignant tumors. Lorlatinib stands out as the most advanced and effective inhibitor currently used in the clinic for the treatment of ALK-positive non-small cell lung cancer. However, resistance to lorlatinib has inevitably manifested over time, with double/triple mutations of G1202, L1196, L1198, C1156 and I1171 frequently observed in clinical practice, and tumors regrow within a short time after treatment with lorlatinib. Therefore, elucidating the mechanism of resistance to lorlatinib is paramount in paving the way for innovative therapeutic strategies and the development of next-generation drugs. In this study, we leveraged multiple computational methodologies to delve into the resistance mechanisms of three specific double mutations of ALKG1202R/L1196M, ALKG1202R/L1198F and ALKI1171N/L1198F to lorlatinib. We analyzed these mechanisms through qualitative (PCA, DCCM) and quantitative (MM/GBSA, US) kinetic analyses. The qualitative analysis shows that these mutations exert minimal perturbations on the conformational dynamics of the structural domains of ALK. The energetic and structural assessments show that the van der Waals interactions, formed by the conserved residue Leu1256 within the ATP-binding site and the residues Glu1197 and Met1199 in the hinge domain with lorlatinib, play integral roles in the occurrence of drug resistance. Furthermore, the US simulation results elucidate that the pathways through which lorlatinib dissociates vary across mutant systems, and the distinct environments during the dissociation process culminate in diverse resistance mechanisms. Collectively, these insights provide important clues for the design of novel inhibitors to combat resistance.

From preclinical efficacy to 2022 (36.7 months median follow -up) updated CROWN trial, lorlatinib is the preferred 1st-line treatment of advanced ALK+ NSCLC.

Six ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, ensartinib) have received first-line treatment indication of advanced ALK+ NSCLC in various countries. In Ba/F3 cells, lorlatinib achieved lowest IC50 among these 6 ALK TKIs against EML4-ALK variant 1 or 3. In 2022, 7 abstracts reported updated efficacy and safety data from CROWN. With a median follow-up time of 36.7 months, the 3-year progression-free survival (PFS) rate was 63.5% for lorlatinib-treated patients and the median PFS of lorlatinib still has not been reached. Importantly, post-lorlatinib treatment median PFS2 was 74.0% at 3-years. Lorlatinib-treated Asian patients achieved similar 3-year PFS rate as overall lorlatinib-treated patients. Median PFS was 33.3 months among lorlatinib-treated EML4-ALK v3 patients. CNS AE occurred fewer than 1 event per patient over the median follow-up time of 36.7 months and most resolved without intervention. Altogether these data affirm our belief that lorlatinib should be the treatment of choice of advanced ALK+ NSCLC.

Sulbactam-durlobactam: A novel ß-lactam-ß-lactamase inhibitor combination targeting carbapenem-resistant Acinetobacter baumannii infections.

Carbapenem-resistant Acinetobacter baumannii (CRAB) is a difficult-to-treat nosocomial pathogen responsible for significant morbidity and mortality. Sulbactam-durlobactam (SUL-DUR), formerly ETX2514SUL, is a novel ß-lactam-ß-lactamase inhibitor designed specifically for the treatment of CRAB infections. The United States Food and Drug Administration (FDA) fast-track approval of SUL-DUR for the treatment of CRAB infections is currently pending after completion of the phase III ATTACK trial, which compared SUL-DUR to colistin, both in combination with imipenem-cilastatin (IMI) for patients with CRAB-associated hospital-acquired bacterial pneumonia, ventilator-associated pneumonia, and bacteremia. The results of this trial demonstrated that SUL-DUR was non-inferior to colistin for CRAB while also possessing a much more favorable safety profile. SUL-DUR was well-tolerated with the most common side effects being headache, nausea, and injection-site phlebitis. With the current landscape of limited effective treatment options for CRAB infections, SUL-DUR represents a promising therapeutic option for the treatment of these severe infections. This review will discuss the pharmacology, spectrum of activity, pharmacokinetics/pharmacodynamics, in vitro and clinical studies, safety, dosing, administration, as well as the potential role in therapy for SUL-DUR.

Carbapenem-sparing beta-lactam/beta-lactamase inhibitors versus carbapenems for bloodstream infections caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae: a systematic review and meta-analysis.

OBJECTIVES: Bloodstream infections (BSIs) caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) have become a worldwide public health threat, and beta-lactam/beta-lactamase inhibitor combinations (BLBLIs) are considered as one reliable carbapenem-sparing antibiotic. However, it is still controversial whether BLBLIs are truly noninferior to carbapenems. Therefore, we conducted this meta-analysis to compare the efficacy of BLBLIs with carbapenems for ESBL-PE BSIs. METHODS: A systematic search of PubMed, Cochrane Library, and Embase was conducted until December 2021 to enroll studies comparing BLBLIs with carbapenems for ESBL-PE BSIs. A subgroup analysis was performed based on the choice of therapy (empirical, definitive, and mixed therapy). The protocol was registered in the International Prospective Register of Systematic Reviews (#CRD42022316011). RESULTS: A total of 2786 patients from one randomized clinical trial and 25 cohorts were included. There was no statistically significant difference between BLBLIs and carbapenems groups in therapeutical response (odds ratio [OR] = 1.19, P = 0.45) and mortality (OR = 1.06, P = 0.68). Furthermore, although the statistical difference was also not found in the subgroup analysis, BLBLIs performed better in definitive therapy than empirical therapy than carbapenems, with a numerically higher therapeutical response (OR = 1.42 vs 0.89) and a mildly lower mortality (OR = 0.85 vs 1.14). CONCLUSION: BLBLIs were noninferior to carbapenems for ESBL-PE BSIs, especially in definitive therapy. BLBLIs may be a valid alternative to spare the use of carbapenems.

An update on lorlatinib: a novel first line treatment for ALK-positive advanced lung cancer.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of ALK-rearranged non-small cell lung cancer (NSCLC), but these patients will eventually develop resistance and progression of disease after 10 months of first-generation and more than 30 months after second-generation TKIs. Lorlatinib is a third-generation highly selective ALK-TKI capable of inducing significant and durable CNS responses and overcoming known ALK resistance mutations. AREAS COVERED: This review summarizes the mechanism of action, efficacy, and safety of lorlatinib in ALK-positive NSCLC. The authors provide their expert opinions on the use of this drug, including its future prospects. EXPERT OPINION: Lorlatinib has shown good efficacy and safety in ALK-positive NSCLC patients progressing to first- and second-generation ALK-TKIs. The phase III trial CROWN evaluating lorlatinib as first-line therapy has provided promising results; however, the comparing arm was crizotinib, supplanted now by second-generation agents. Whether lorlatinib can replace them as upfront strategy is a relevant question that still remains open. In our opinion, longer follow-up and face-to-face studies are required to determine which is the best treatment sequence strategy. The advent of liquid biopsy will contribute to treatment tailoring according to the genomic profile at progression.

Sulopenem or Ciprofloxacin for the Treatment of Uncomplicated Urinary Tract Infections in Women: A Phase 3, Randomized Trial.

BACKGROUND: There are limited treatment options for uncomplicated urinary tract infection (uUTI) caused by resistant pathogens. Sulopenem etzadroxil/probenecid (sulopenem) is an oral thiopenem antibiotic active against multidrug-resistant pathogens that cause uUTIs. METHODS: Patients with uUTI were randomized to 5 days of sulopenem or 3 days of ciprofloxacin. The primary endpoint was overall success, defined as both clinical and microbiologic response at day 12. In patients with ciprofloxacin-nonsusceptible baseline pathogens, sulopenem was compared for superiority over ciprofloxacin; in patients with ciprofloxacin-susceptible pathogens, the agents were compared for noninferiority. Using prespecified hierarchical statistical testing, the primary endpoint was tested in the combined population if either superiority or noninferiority was declared in the nonsusceptible or susceptible population, respectively. RESULTS: In the nonsusceptible population, sulopenem was superior to ciprofloxacin, 62.6% vs 36.0% (difference, 26.6%; 95% confidence interval [CI], 15.1 to 7.4; P <.001). In the susceptible population, sulopenem was not noninferior to ciprofloxacin, 66.8% vs 78.6% (difference, -11.8%; 95% CI, -18.0 to 5.6). The difference was driven by a higher rate of asymptomatic bacteriuria (ASB) post-treatment in patients on sulopenem. In the combined analysis, sulopenem was noninferior to ciprofloxacin, 65.6% vs 67.9% (difference, -2.3%; 95% CI, -7.9 to 3.3). Diarrhea occurred more frequently with sulopenem (12.4% vs 2.5%). CONCLUSIONS: Sulopenem was noninferior to ciprofloxacin in the treatment of uUTIs. Sulopenem was superior to ciprofloxacin in patients with uUTIs due to ciprofloxacin-nonsusceptible pathogens. Sulopenem was not noninferior in patients with ciprofloxacin-susceptible pathogens, driven largely by a lower rate of ASB in those who received ciprofloxacin. CLINICAL TRIAL REGISTRATION: NCT03354598.

Oral IRAK4 inhibitor BAY-1834845 prevents acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a lethal clinical entity that has become an emergency event with the outbreak of COVID-19. However, to date, there are no well-proven pharmacotherapies except dexamethasone. This study is aimed to evaluate IRAK4 inhibitors as a potential treatment for ARDS-cytokine release syndrome (CRS). We applied two IRAK4 inhibitors, BAY-1834845 and PF-06650833 to an inhaled lipopolysaccharide (LPS)-induced ARDS mouse model with control of high dose dexamethasone (10 mg/kg). Unexpectedly, although both compounds had excellent IC50 on IRAK4 kinase activity, only BAY-1834845 but not PF-06650833 or high dose dexamethasone could significantly prevent lung injury according to a blinded pathology scoring. Further, only BAY-1834845 and BAY-1834845 combined with dexamethasone could effectively improve the injury score of pre-existed ARDS. Compared with PF-06650833 and high dose dexamethasone, BAY-1834845 remarkably decreased inflammatory cells infiltrating lung tissue and neutrophil count in BALF. BAY-1834845, DEX, and the combination of the two agents could decrease BALF total T cells, monocyte, and macrophages. In further cell type enrichment analysis based on lung tissue RNA-seq, both BAY-1834845 and dexamethasone decreased signatures of inflammatory cells and effector lymphocytes. Interestingly, unlike the dexamethasone group, BAY-1834845 largely preserved the signatures of naïve lymphocytes and stromal cells such as endothelial cells, chondrocytes, and smooth muscle cells. Differential gene enrichment suggested that BAY-1834845 downregulated genes more efficiently than dexamethasone, especially TNF, IL-17, interferon, and Toll-like receptor signaling.

Nirmatrelvir Use and Severe Covid-19 Outcomes during the Omicron Surge.

BACKGROUND: The oral protease inhibitor nirmatrelvir has shown substantial efficacy in high-risk, unvaccinated patients infected with the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Data regarding the effectiveness of nirmatrelvir in preventing severe coronavirus disease 2019 (Covid-19) outcomes from the B.1.1.529 (omicron) variant are limited. METHODS: We obtained data for all members of Clalit Health Services who were 40 years of age or older at the start of the study period and were assessed as being eligible to receive nirmatrelvir therapy during the omicron surge. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association of nirmatrelvir treatment with hospitalization and death due to Covid-19, with adjustment for sociodemographic factors, coexisting conditions, and previous SARS-CoV-2 immunity status. RESULTS: A total of 109,254 patients met the eligibility criteria, of whom 3902 (4%) received nirmatrelvir during the study period. Among patients 65 years of age or older, the rate of hospitalization due to Covid-19 was 14.7 cases per 100,000 person-days among treated patients as compared with 58.9 cases per 100,000 person-days among untreated patients (adjusted hazard ratio, 0.27; 95% confidence interval [CI], 0.15 to 0.49). The adjusted hazard ratio for death due to Covid-19 was 0.21 (95% CI, 0.05 to 0.82). Among patients 40 to 64 years of age, the rate of hospitalization due to Covid-19 was 15.2 cases per 100,000 person-days among treated patients and 15.8 cases per 100,000 person-days among untreated patients (adjusted hazard ratio, 0.74; 95% CI, 0.35 to 1.58). The adjusted hazard ratio for death due to Covid-19 was 1.32 (95% CI, 0.16 to 10.75). CONCLUSIONS: Among patients 65 years of age or older, the rates of hospitalization and death due to Covid-19 were significantly lower among those who received nirmatrelvir than among those who did not. No evidence of benefit was found in younger adults.

Bad news for Paxlovid? Resistance may be coming.

In lab studies, SARS-CoV-2 finds ways to evade key drug. Some of the viral mutations are already found in people.

Early clinical experience with nirmatrelvir/ritonavir for the treatment of COVID-19 in solid organ transplant recipients.

Nirmatrelvir/ritonavir (NR) use has not yet been described in solid organ transplant recipients (SOTRs) with mild COVID-19. The objective was to evaluate outcomes among SOTR and describe the drug-drug interaction of NR. This is an IRB-approved, retrospective study of all adult SOTR on a calcineurin inhibitor (CNI) or mammalian target of rapamycin inhibitor who were prescribed NR between December 28, 2021 and January 6, 2022. A total of 25 adult SOTR were included (n = 21 tacrolimus, n = 4 cyclosporine, n = 3 everolimus, n = 1 sirolimus). All patients were instructed to follow the following standardized protocol during treatment with 5 days of NR: hold tacrolimus or mTOR inhibitor or reduce cyclosporine dose to 20% of baseline daily dose. Four patients (16%) were hospitalized by day 30; one for infectious diarrhea and three for symptoms related to COVID-19. No patients died within 30 days of receipt of NR. Median tacrolimus level pre- and post-NR were 7.4 ng/ml (IQR, 6.6-8.6) and 5.2 (IQR, 3.6-8.7), respectively. Four patients experienced a supratherapeutic tacrolimus concentration after restarting tacrolimus post-NR. Our results show the clinically significant interaction between NR and immunosuppressive agents can be reasonably managed with a standardized dosing protocol. Prescribers should carefully re-introduce CNI after the NR course is complete.