Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC.

BACKGROUND: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC). METHODS: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR-mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review. RESULTS: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR-related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib. CONCLUSIONS: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR-mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).

The HIV-1 capsid serves as a nanoscale reaction vessel for reverse transcription.

The viral capsid performs critical functions during HIV-1 infection and is a validated target for antiviral therapy. Previous studies have established that the proper structure and stability of the capsid are required for efficient HIV-1 reverse transcription in target cells. Moreover, it has recently been demonstrated that permeabilized virions and purified HIV-1 cores undergo efficient reverse transcription in vitro when the capsid is stabilized by addition of the host cell metabolite inositol hexakisphosphate (IP6). However, the molecular mechanism by which the capsid promotes reverse transcription is undefined. Here we show that wild type HIV-1 virions can undergo efficient reverse transcription in vitro in the absence of a membrane-permeabilizing agent. This activity, originally termed "natural endogenous reverse transcription" (NERT), depends on expression of the viral envelope glycoprotein during virus assembly and its incorporation into virions. Truncation of the gp41 cytoplasmic tail markedly reduced NERT activity, suggesting that gp41 licenses the entry of nucleotides into virions. By contrast to reverse transcription in permeabilized virions, NERT required neither the addition of IP6 nor a mature capsid, indicating that an intact viral membrane can substitute for the function of the viral capsid during reverse transcription in vitro. Collectively, these results demonstrate that the viral capsid functions as a nanoscale container for reverse transcription during HIV-1 infection.

Management of KRAS-mutated non-small cell lung cancer.

Kirsten rat sarcoma virus (KRAS) is the most frequently mutated oncogene in human cancers, particularly in non-small cell lung cancer (NSCLC), where mutations are present in 32% of lung adenocarcinoma and 4% of squamous cell lung cancer. The most common KRAS variant is KRAS G12C, which accounts for nearly 40% of all KRAS mutations. Although it is the most common oncogenic driver in NSCLC, KRAS was considered a "nondruggable target" until recently, owing to the lack of any progress in developing targeted therapies for this oncogene. With the recent development and approval of selective KRAS G12C inhibitors such as sotorasib and adagrasib for the treatment of advanced or metastatic NSCLC in the second-line setting and beyond, the standard of care for managing these tumors has undergone a significant change. Mechanisms of resistance to KRAS G12C inhibitors are highly heterogeneous, including both on-target and off-target resistance as well as morphologic switching, thus limiting the activity of these drugs when used as monotherapy. New-generation inhibitors and different combination strategies are being developed in early-phase trials to overcome or delay the onset of resistance as well as to target non-G12C mutations. Owing to the biological heterogeneity of KRAS-mutant NSCLC, treatment will likely need to be individualized based on factors such as co-occurring mutations.

Tracheal ulcer development from high volume, low-pressure cuffed endotracheal tubes.

INTRODUCTION: Iatrogenic injury to the larynx, particularly the vocal cords from prolonged intubation, has been well-studied; however, tracheal injuries are rarely reported. This study investigates the effectiveness of cuffed, high-volume, low-pressure endotracheal tubes in preventing the development of tracheal ulcers in intubated subjects. METHODS: A retrospective, IRB-approved review was performed on 1355 subjects who underwent percutaneous tracheostomy from 2002 to 2018. The presence and severity of tracheal ulcers were collected using documentation and photos during percutaneous tracheostomy placement. Primary outcome measures included: the length of time on a ventilator until tracheostomy (LOVT), length of hospitalization (LOH), and mortality in relationship to the severity of the tracheal injury. Data was reported as n (%) and median (IQR). The differences in means between groups were analyzed by ANOVA and Chi-square test with an alpha of 0.05. RESULTS: 206 subjects met the inclusion criteria; 65 subjects had an absence of tracheal injury, and 141 subjects developed tracheal ulcers. Subjects with tracheal ulcers were grouped by the following severity scale: no ulcer; mild ulcer (minimal mucosal erosion with exudate); moderate ulcer (mucosal erosion); and severe (tracheal ring exposure). There were no statistically significant differences in age (p = 0.99), gender (p = 0.83), BMI (p = 0.44), LOH (p = 0.88), LOVT (p = 0.93), and mortality (p = 0.306) between subjects with differing severity of ulcers. The average annual incidence of clinically significant ulcers (moderate and severe) was 2.2 %. CONCLUSIONS: The lack of statistical correlation between the duration of intubation and tracheal ulcer severity, along with a low annual incidence of tracheal ulcers, supports the improved safety of high-volume, low-pressure cylindrical, cuffed endotracheal tubes. This study is among the first to specifically focus on injuries at the level of the cuff and tip of endotracheal tubes with implications in preventive measures and potential product design changes.

Role of CD44 in Chemotherapy Treatment Outcome: A Scoping Review of Clinical Studies.

Cluster of differentiation 44 (CD44), a cell surface adhesion molecule overexpressed in cancer stem cells, has been implicated in chemoresistance. This scoping review, following PRISMA-ScR guidelines, systematically identified and evaluated clinical studies on the impact of CD44 expression on chemotherapy treatment outcomes across various cancer types. The search encompassed PubMed (1985-2023) and SCOPUS (1936-2023) databases, yielding a total of 12,659 articles, of which 40 met the inclusion criteria and were included in the qualitative synthesis using a predefined data extraction table. Data collected included the cancer type, sample size, interventions, control, treatment outcome, study type, expression of CD44 variants and isoforms, and effect of CD44 on chemotherapy outcome. Most of the studies demonstrated an association between increased CD44 expression and negative chemotherapeutic outcomes such as shorter overall survival, increased tumor recurrence, and resistance to chemotherapy, indicating a potential role of CD44 upregulation in chemoresistance in cancer patients. However, a subset of studies also reported non-significant relationships or conflicting results. In summary, this scoping review highlighted the breadth of the available literature investigating the clinical association between CD44 and chemotherapeutic outcomes. Further research is required to elucidate this relationship to aid clinicians in managing CD44-positive cancer patients.

The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance.

Antigen-presenting cells (APCs) induce T cell activation as well as T cell tolerance. The molecular basis of the regulation of this critical 'decision' is not well understood. Here we show that HDAC11, a member of the HDAC histone deacetylase family with no prior defined physiological function, negatively regulated expression of the gene encoding interleukin 10 (IL-10) in APCs. Overexpression of HDAC11 inhibited IL-10 expression and induced inflammatory APCs that were able to prime naive T cells and restore the responsiveness of tolerant CD4+ T cells. Conversely, disruption of HDAC11 in APCs led to upregulation of expression of the gene encoding IL-10 and impairment of antigen-specific T cell responses. Thus, HDAC11 represents a molecular target that influences immune activation versus immune tolerance, a critical 'decision' with substantial implications in autoimmunity, transplantation and cancer immunotherapy.

Intravenous Versus Oral Acetaminophen in Ambulatory Surgical Center Laparoscopic Cholecystectomies: A Retrospective Analysis.

STUDY OBJECTIVE: The primary aim was to compare postoperative pain scores in patients undergoing laparoscopic cholecystectomy and receiving intravenous (IV) or oral (PO) acetaminophen (APAP) as part of a multimodal analgesic regimen to examine whether PO APAP is non-inferior to IV APAP. DESIGN: Retrospective analysis. SETTING: Ambulatory surgical center (ASC) in an academic setting. PATIENTS: 579 patients (18-70 years old), American Society of Anesthesiologists physical status I-III, undergoing laparoscopic cholecystectomy. INTERVENTIONS: Patients received 1,000 mg IV APAP intraoperatively (n = 319) or 1,000 mg PO APAP preoperatively (n = 260). MEASUREMENTS: The primary outcome was the median difference in post-anesthesia care unit (PACU) end-pain scores between the groups. Median pain scores were also compared on PACU admission, and at 15, 30, 45, and 60 minutes. Additional measures include PACU rescue-analgesia consumption, time to first PACU rescue analgesia, intraoperative use of opioid and nonopioid analgesics, PACU length of stay, and PACU rescue nausea and vomiting therapy. MAIN RESULTS: In both groups, the PACU median end-pain score was 2. The 90% confidence interval (CI) for difference in median pain scores between groups was [0, 0]; the CI upper limit was below the non-inferior margin of 1 pain-score point, indicating PO APAP's non-inferiority to IV APAP. There were no statistically significant differences in the percentages of patients receiving PACU hydromorphone equivalents between the IV and PO groups (75% vs. 77%, P = 0.72) or in the mean dose received (0.5 mg vs. 0.5 mg, P = 0.66). CONCLUSION: Single-dose PO APAP is non-inferior to IV APAP for postoperative analgesia in ASC laparoscopic cholecystectomy patients. The value of single-dose IV APAP in this population should be further explored.

Normalization of Left Ventricular Ejection Fraction and Incidence of Appropriate Antitachycardia Therapy in Patients With Implantable Cardioverter Defibrillator for Primary Prevention of Sudden Death.

BACKGROUND: Patients with severely depressed left ventricular ejection fractions (LVEFs) receive implantable cardioverter-defibrillators (ICDs) for the primary prevention of sudden death. In some patients, however, LVEF may improve or even normalize over time. Limited data are available on the incidence of appropriate antitachycardia therapy, including pacing and shock, in these patients. METHODS AND RESULTS: We retrospectively identified consecutive patients at our institution with an ICD for primary prevention who had LVEF measurement available at initial implantation and at the time of generator replacement. None of these patients had ever received appropriate antitachycardia therapy before generator replacement. The incidence of appropriate antitachycardia therapy after generator replacement was assessed. Of the 125 patients who received generator replacement, 53 (42%) received an ICD and 72 (58%) a cardiac resynchronization therapy-defibrillator (CRT-D). Among them, 30 (21%) had LVEF normalized to ≥50%, 25 (17%) had LVEF partially improved to 36%-49%, and 70 (63%) had LVEF that remained depressed at ≤35%. During an overall follow-up period of 25 ± 18 months, none of the individuals with normalized LVEF experienced appropriate antitachycardia therapy regardless of ICD or CRT-D. Meanwhile, 20% of patients with LVEF at 36%-49% and 14% of patients with LVEF at ≤35% received appropriate ICD therapy. The omnibus P value for any differences among the 3 LVEF groups was 0.046 for the entire cohort, 0.01 for ICD, and 0.15 for CRT-D patients. CONCLUSIONS: These preliminary data suggest that patients with reduced LVEF and primary-prevention ICDs who normalize their LVEF over time may be at lower risk of appropriate antitachycardia therapy.

Knee Pain and Patellofemoral Symptoms in Patients With Cerebral Palsy.

BACKGROUND: Knee pain in cerebral palsy (CP) is associated with increased patellofemoral forces present when walking with flexed knees. In typically developing children, knee pain and patellofemoral dysfunction are associated with obesity, genu valgum, femoral anteversion, and external tibial torsion. These problems are also common in CP, and may contribute to knee problems in this population. The purposes of this study were to define the prevalence of knee pain and patellofemoral dysfunction in children with CP, and to identify physical and gait characteristics (using 3-dimensional gait analysis data) that predispose them to such problems. METHODS: Retrospective review of 121 children with CP, Gross Motor Function Classification System level I to IV, who underwent computerized gait analysis testing. Demographics, range of motion, body mass index and hip, knee, and ankle kinematics were compared between subjects with and without knee pain. RESULTS: Twenty-five of 121 subjects (21%) reported knee pain at the time of testing. Three of 121 subjects (2%) had a history of patellar subluxation/dislocation. Age and sex were significantly related to presence of knee pain. The likelihood of knee pain was almost 5 times higher in females (odds ratio=4.9, [95% confidence interval, 1.8-13.3], P=0.002), with a prevalence of 40% (17/42) in females versus 10% (8/79) in males. The likelihood of knee pain increased with age by approximately 13% per year (odds ratio=1.13, [95% confidence interval, 1.00-1.28], P=0.058). Malignant malalignment syndrome showed a potential relationship to more severe knee pain (P=0.05), which warrants further investigation. Body mass index, pes valgus, and degree of stance knee flexion showed no statistically significant relationships to knee pain (P>0.16). CONCLUSIONS: The prevalence of knee pain in ambulatory patients with CP is approximately 21%. Patellar subluxation (2%) and dislocation are rare in these patients. Knee pain is not always related to crouch, femoral anteversion, external tibial torsion, genu valgum, or pes valgus. Knee pain in these patients is more prevalent in females, and increases with increasing age. LEVEL OF EVIDENCE: Level III-case-control study.

Risks and benefits of phase 1 clinical trial participation.

BACKGROUND: The results from phase 1 clinical trials can allow new treatments to progress further in drug development or halt that process altogether. At the forefront of phase 1 clinical trials is the safety of every patient participant, which is particularly true when testing new oncologic treatments in which patients may risk potentially toxic treatments in the hope of slowing the progression of or even curing their disease. METHODS: We explore the benefits and risks that patients experience when participating in phase 1 clinical trials. RESULTS: Rules and regulations have been put into place to protect the safety and interests of patients while undergoing clinical trials. Selecting patients with cancer who will survive long enough to accrue data for these trials continues to be challenging. New prognostic models have been validated to help health care professionals select those patients who will likely benefit from participation in phase 1 trials. There also are long-lasting positive and negative impacts on those patients who choose to participate in phase 1 clinical trials. CONCLUSIONS: Modern phase 1 clinical trials represent a therapeutic option for many patients who progress through frontline therapy for their malignancies. Recent phase 1 clinical trials testing targeted therapies have increased responses in many diseases in which other lines of therapy have failed. Patients still face many risks and benefits while enrolled in a phase 1 trial, but the likelihood of treatment response in the era of rational, targeted therapy is increased when compared with the era of cytotoxic therapy.

Defining the Parameters for Endovenous Microwave Ablation to Achieve Equivalence With Endovenous Laser Ablation, Using the Porcine Liver Model.

AIMS: Endovenous microwave ablation (EMWA) is an endovenous thermoablation (EVTA) system to ablate incompetent truncal veins. Early results suggest that EMWA uses more power than endovenous laser ablation (EVLA) to get the same results. We aimed to define the parameters for EMWA, which give the same tissue ablation as EVLA, using the validated porcine liver model. METHODS: EVLA (1470 nm 600 micron radial fibre) treatments were performed at 6 W, 8 W and 10 W, at pullback speeds of 6, 7, 8 and 9 s/cm, giving Linear Endovenous Energy Densities (LEEDs) between 36 - 90 J/cm. Each combination of power and pullback was repeated 5 times. We then used EMWA in the same model. Powers of 35-75 W and pullback speeds of 4-9 s/cm were used (LEEDs 140-675 J/cm). Ablation tracts from both devices were analysed by 2 blinded observers, noting thermal spread and carbonisation. RESULTS: For each commonly used parameter for EVLA, we identified a range of parameters for EMWA that produced similar tissue ablation in the porcine liver model. To keep the pullback speeds within the usual range, powers of 35-75 W were needed with EMWA, with mean EMWA LEEDs 3.9 - 5.8 times higher than EVLA LEEDs. We found the quicker the pullback speed, the higher the multiple of EMWA LEED we needed to get the same effect. CONCLUSION: We have identified parameters for EMWA that gave equivalent tissue ablation in the porcine liver model to commonly used parameters used for EVLA. These need to be validated clinically, but as the model used has already been validated against clinical outcome in endovenous thermal ablation, there is little reason to suspect that these results would not be valid. As the power during EMWA is higher than EVLA, EVMA LEEDs are approximately 4-6 times higher than EVLA LEEDs to achieve the same thermal effect on the tissues.

Efficacy of Mobocertinib and Amivantamab in Patients With Advanced Non-Small Cell Lung Cancer With EGFR Exon 20 Insertions Previously Treated With Platinum-Based Chemotherapy: An Indirect Treatment Comparison.

INTRODUCTION: Exon 20 insertions (ex20ins) mutations of the EGFR gene account for 1% to 2% of all non-small-cell lung cancers (NSCLCs). Targeted therapies have been developed to treat this cancer type but have not been studied in head-to-head trials. Our objective was to use a matching-adjusted indirect comparison (MAIC) to assess the efficacy of mobocertinib and amivantamab in patients with NSCLC EGFR ex20ins mutations who were previously treated with platinum-based chemotherapy. MATERIALS AND METHODS: An unanchored MAIC was conducted to estimate the treatment effects of mobocertinib and amivantamab using individual-level data from the mobocertinib phase I/II single-arm trial (NCT02716116) and published data from the amivantamab single-arm CHRYSALIS trial (NCT02609776). Confirmed overall response rate (cORR), progression-free survival (PFS), overall survival (OS), and duration of response (DoR) were assessed. RESULTS: Both trials were comparable in terms of study population, study design, and outcome definitions and included 114 patients who received mobocertinib and 114 patients who received amivantamab. After MAIC weighting, all reported baseline characteristics were balanced between mobocertinib and amivantamab. The weighted odds ratio (OR) [95% confidence interval (CI)] comparing mobocertinib to amivantamab was 0.56 (0.30-1.04) for independent review committee (IRC)-assessed cORR and 0.98 (0.53-1.82) for investigator (INV)-assessed cORR. The weighted hazard ratio (HR) comparing mobocertinib to amivantamab was 0.74 (0.51-1.07) for IRC-assessed PFS, 0.92 (0.57-1.48) for OS, and 0.59 (0.30-1.18) for INV-assessed DoR. CONCLUSION: MAIC analysis showed that mobocertinib and amivantamab had similar efficacy in patients with NSCLC harboring EGFR ex20ins mutations whose disease progressed during or after platinum-based chemotherapy. These findings may benefit patients by supporting future treatment options.

Subcutaneous Versus Intravenous Amivantamab, Both in Combination With Lazertinib, in Refractory Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: Primary Results From the Phase III PALOMA-3 Study.

PURPOSE: Phase III studies of intravenous amivantamab demonstrated efficacy across epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy. PATIENTS AND METHODS: Patients with EGFR-mutated advanced NSCLC who progressed after osimertinib and platinum-based chemotherapy were randomly assigned 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Coprimary pharmacokinetic noninferiority end points were trough concentrations (Ctrough; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUCD1-D15). Key secondary end points were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory end point. RESULTS: Overall, 418 patients underwent random assignment (subcutaneous group, n = 206; intravenous group, n = 212). Geometric mean ratios of Ctrough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04 to 1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27 to 1.61) at cycle-4-day-1; the cycle-2 AUCD1-D15 was 1.03 (90% CI, 0.98 to 1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42 to 0.92; nominal P = .02). Fewer patients in the subcutaneous group experienced infusion-related reactions (IRRs; 13% v 66%) and venous thromboembolism (9% v 14%) versus the intravenous group. Median administration time for the first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab and to 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; the end-of-treatment rates were 85% and 35%, respectively. CONCLUSION: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced IRRs, increased convenience, and prolonged survival.

Proposed Implementation of a Patient-Centered Self-Assessment Tool for Patients with Neuroendocrine Tumors among Academic and Community Practice Sites: The City of Hope Model.

Neuroendocrine tumors are a rare type of cancer found in hormone-producing cells throughout the body. Research on disease-specific patient education assessments in this population is lacking. We previously demonstrated the feasibility and validity of NET VITALS, a patient-centered self-assessment designed to improve patients' knowledge of their neuroendocrine tumor diagnosis/treatment and facilitate communication with their physician. In this report, we provide a brief overview of patient assessments that have been used for patients with neuroendocrine tumors. We summarize NET VITALS and present a proposed infrastructure for its implementation into standard clinical care in both academic and community practice settings at City of Hope. Incorporating NET VITALS into standard of care treatment for patients with neuroendocrine tumors may improve patients' overall clinical care experience.

Real-World Response and Outcomes in Patients With NSCLC With EGFR Exon 20 Insertion Mutations.

Introduction: This study describes treatment patterns and outcomes in patients with NSCLC with EGFR exon 20 insertions (EGFRex20ins) in the United States. Methods: The Flatiron Health electronic health record database was used to select three cohorts among patients diagnosed with NSCLC with EGFRex20ins (January 1, 2011-February 29, 2020): (1) first-line (1L) or patients receiving 1L therapy after documented EGFRex20ins; (2) second or later-line (≥2L) or patients receiving ≥2L therapy after documented EGFRex20ins; and (3) ≥2L postplatinum trial-aligned, or ≥2L patients previously treated with platinum chemotherapy whose baseline characteristics aligned with key eligibility criteria (initiating new treatment after documented EGFRex20ins and ≥1 previous treatment excluding mobocertinib or amivantamab) of the mobocertinib trial NCT02716116. Real-world end points were confirmed overall response rate, overall survival, and progression-free survival. Results: Of 237 patients with EGFRex20ins-mutated NSCLC, 129 and 114 patients were included in the 1L and ≥2L cohorts, respectively. In 1L patients, platinum chemotherapy plus nonplatinum chemotherapy (31.0%) and EGFR tyrosine kinase inhibitors (28.7%) were the most common regimens. In ≥2L patients, immuno-oncology monotherapy (28.1%) and EGFR tyrosine kinase inhibitors (17.5%) were the most common index treatments. For any 1L, ≥2L, and ≥2L postplatinum trial-aligned patients, the confirmed overall response rate was 18.6%, 9.6%, and 14.0%, respectively; the median overall survival was 17.0, 13.6, and 11.5 months; the median progression-free survival was 5.2, 3.7, and 3.3 months, respectively. Conclusions: The outcomes for patients with NSCLC with EGFRex20ins were poor. This real-world study provides a benchmark on treatment outcomes in this patient population and highlights the unmet need for improved therapeutic options.

The HIV-1 capsid serves as a nanoscale reaction vessel for reverse transcription.

The viral capsid performs critical functions during HIV-1 infection and is a validated target for antiviral therapy. Previous studies have established that the proper structure and stability of the capsid are required for efficient HIV-1 reverse transcription in target cells. Moreover, it has recently been demonstrated that permeabilized virions and purified HIV-1 cores undergo efficient reverse transcription in vitro when the capsid is stabilized by addition of the host cell metabolite inositol hexakisphosphate (IP6). However, the molecular mechanism by which the capsid promotes reverse transcription is undefined. Here we show that wild type HIV-1 particles can undergo efficient reverse transcription in vitro in the absence of a membrane-permeabilizing agent. This activity, originally termed "natural endogenous reverse transcription" (NERT), depends on expression of the viral envelope glycoprotein during virus assembly and its incorporation into virions. Truncation of the gp41 cytoplasmic tail markedly reduced NERT activity, indicating that gp41 permits the entry of nucleotides into virions. Protease treatment of virions markedly reduced NERT suggesting the presence of a proteinaceous membrane channel. By contrast to reverse transcription in permeabilized virions, NERT required neither the addition of IP6 nor a mature capsid, indicating that an intact viral membrane can substitute for the function of the viral capsid during reverse transcription in vitro. Collectively, these results demonstrate that the viral capsid functions as a nanoscale container for reverse transcription during HIV-1 infection.

Comparative effectiveness of mobocertinib and standard of care in patients with NSCLC with EGFR exon 20 insertion mutations: An indirect comparison.

INTRODUCTION: Mobocertinib is a novel, first-in-class, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to selectively target in-frame EGFR exon 20 insertions (ex20ins). Comparative effectiveness data for mobocertinib versus real-world treatments are lacking in this rare population. This study compared data for mobocertinib reported in a Phase I/II single-arm clinical trial with an external control group consisting of patients who received available treatment in the real-world setting in the United States (US). MATERIALS AND METHODS: The mobocertinib group included platinum-pretreated patients with advanced EGFR ex20ins non-small cell lung cancer (NSCLC) receiving mobocertinib 160 mg QD in an ongoing, single-arm, phase 1/2 clinical trial (NCT02716116; n = 114). The real-world data (RWD) group included platinum-pretreated patients with advanced EGFR ex20ins-mutant NSCLC from the Flatiron Health database (n = 50). Inverse probability treatment weighting based on the propensity score method controlled for potential confounding between groups. Confirmed overall response rate (cORR), progression-free survival (PFS), and overall survival (OS) were compared between groups. RESULTS: After weighting, baseline characteristics were balanced. Patients in the RWD group received EGFR TKI (20 %), immuno-oncology therapy (40 %), or any regimens containing chemotherapy (40 %) in the second- or later-line setting. In the mobocertinib and RWD groups, respectively, cORR was 35.1 % and 11.9 % (odds ratio: 3.75 [95 % confidence interval (CI): 2.05, 6.89]); median PFS was 7.3 and 3.3 months (hazard ratio [HR]: 0.57 [95 % CI: 0.36, 0.90]); and median OS was 24.0 and 12.4 months (HR: 0.53 [95 % CI: 0.33, 0.83]) after weighting. DISCUSSION: Mobocertinib showed substantially improved outcomes versus an external control group using available therapies in platinum-pretreated patients with EGFR ex20ins-mutant NSCLC. In the absence of comparative evidence from randomized trials, these findings help elucidate potential benefits of mobocertinib in this rare population.

Safety, Tolerability, and Antitumor Activity of Zipalertinib Among Patients With Non-Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20 Insertions.

PURPOSE: Although several agents targeting epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to the inhibition of wild-type (WT) EGFR are common with these agents and affect overall tolerability. Zipalertinib (CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) with a novel pyrrolopyrimidine scaffold leading to enhanced selectivity for EGFR ex20ins-mutant versus WT EGFR with potent inhibition of cell growth in EGFR ex20ins-positive cell lines. METHODS: This phase 1/2a study of zipalertinib enrolled patients with recurrent or metastatic EGFR ex20ins-mutant non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. RESULTS: Seventy-three patients were treated with zipalertinib at dose levels including 30, 45, 65, 100, and 150 mg orally twice a day. Patients were predominantly female (56%), had a median age of 64 years, and were heavily pretreated (median previous systemic therapies 2, range 1-9). Thirty six percent of patients had received previous non-ex20ins EGFR TKIs and 3/73 (4.1%) patients received previous EGFR ex20ins TKIs. The most frequently reported treatment-related adverse events of any grade included rash (80%), paronychia (32%), diarrhea (30%), and fatigue (21%). No cases of grade 3 or higher drug-related rash or diarrhea were observed at 100 mg twice a day or below. Objective responses occurred across all zipalertinib dose levels tested, with confirmed partial response (PR) observed in 28/73 (38.4%) response-evaluable patients. Confirmed PRs were seen in 16/39 (41%) response-evaluable patients at the dose of 100 mg twice a day. CONCLUSION: Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash.

Characterization and management of adverse events observed with mobocertinib (TAK-788) treatment for EGFR exon 20 insertion-positive non-small cell lung cancer.

BACKGROUND: Mobocertinib has demonstrated durable clinical benefit in platinum-pretreated patients (PPP) with epidermal growth factor receptor exon 20 insertion-positive non-small cell lung cancer (NSCLC). RESEARCH DESIGN AND METHODS: Pooled safety analysis of two studies included patients with NSCLC (N = 257) treated with the recommended phase 2 dose (RP2D) of mobocertinib (160 mg once daily). We report overall safety (treatment-emergent adverse events [TEAEs]) in the RP2D population; characterization of GI and skin-related events in 114 PPP from a phase 1/2 study (NCT02716116); and clinical activity in PPP with and without dose reductions due to TEAEs. RESULTS: In the RP2D population (N = 257), the most common TEAEs were diarrhea (93%), nausea (47%), rash (38%), and vomiting (37%). In PPP (N = 114), median times to diarrhea onset and resolution were 5 and 2 days, respectively. Median times to onset and resolution of skin-related events were 9 and 78 days, respectively. Among PPP with (n = 29) or without (n = 85) dose reductions due to TEAEs, overall response rates were 21% and 31% and median durations of response were 5.7 and 17.5 months, respectively. CONCLUSIONS: GI and skin-related events are common with mobocertinib; minimizing dose reductions with proactive management may improve clinical outcomes. TRIAL REGISTRATION: NCT02716116; NCT03807778.

Mobocertinib is a treatment for patients with a certain type of lung cancer. We analyzed the safety of mobocertinib in 257 patients with lung cancer. The most common side effects with mobocertinib were diarrhea, nausea, vomiting, and skin rash. In 114 patients with lung cancer who were treated in the past with chemotherapy that included platinum-based drugs, diarrhea started after about 5 days of mobocertinib treatment and went away in about 2 days. Skin-related side effects started after about 9 days and went away in about 2.5 months. One-fifth of patients who had to receive a smaller amount of mobocertinib because of side effects responded to treatment compared with one-third of patients who received the recommended mobocertinib amount. Managing side effects quickly can better help patients with lung cancer who are treated with mobocertinib.

Tucatinib and Trastuzumab for Previously Treated Human Epidermal Growth Factor Receptor 2-Positive Metastatic Biliary Tract Cancer (SGNTUC-019): A Phase II Basket Study.

PURPOSE: To evaluate the efficacy and safety of tucatinib and trastuzumab in patients with previously treated human epidermal growth factor receptor 2-positive (HER2+) metastatic biliary tract cancer (mBTC). METHODS: SGNTUC-019 (ClinicalTrials.gov identifier: NCT04579380) is an open-label phase II basket study evaluating the efficacy and safety of tucatinib and trastuzumab in patients with HER2-altered solid tumors. In the biliary tract cancer cohort, patients had previously treated HER2 overexpressing or amplified (HER2+) tumors (identified with local testing) with no prior HER2-directed therapy. The primary end point was confirmed objective response rate (cORR) per investigator assessment. Patients were treated on a 21-day cycle with tucatinib (300 mg orally twice daily) and trastuzumab (8 mg/kg intravenously followed by 6 mg/kg every 3 weeks). RESULTS: Thirty patients were enrolled. As of data cutoff (January 30, 2023), the median duration of follow-up was 10.8 months. The cORR was 46.7% (90% CI, 30.8 to 63.0), with a disease control rate of 76.7% (90% CI, 60.6 to 88.5). The median duration of response and progression-free survival were 6.0 months (90% CI, 5.5 to 6.9) and 5.5 months (90% CI, 3.9 to 8.1), respectively. At data cutoff, 15 patients (50.0%) had died, and the estimated 12-month overall survival rate was 53.6% (90% CI, 36.8 to 67.8). The two most common treatment-emergent adverse events (TEAEs) were pyrexia (43.3%) and diarrhea (40.0%). Grade ≥3 TEAEs were reported in 18 patients (60.0%), with the most common being cholangitis, decreased appetite, and nausea (all 10.0%), which were generally not treatment related. TEAEs led to treatment regimen discontinuation in one patient, and there were no deaths due to TEAEs. CONCLUSION: Tucatinib combined with trastuzumab had clinically significant antitumor activity and was well tolerated in patients with previously treated HER2+ mBTC.