Citations

Abstract Background Mycobacterium abscessus complex (MABC) is a difficult-to-treat infection due to antibiotic resistance. Our study aimed to assess omadacycline’s (OMC) clinical and microbiological outcomes for the treatment of pulmonary MABC. Methods A retrospective study was carried out across 12 US medical institutions from 1/2018-4/2023 to examine the clinical outcomes, and tolerability of OMC treatment for pulmonary MABC. Patients aged ≥ 18 years who were treated with OMC for ≥ 3 months were included. The primary outcome was clinical success at 3, 6, and 12 months. The secondary outcomes were sputum culture conversion rate, adverse effects, and clinical success by subspecies and macrolide susceptibility. Results Thirty-five patients were included in this analysis. Most patients were female (74.3%) and Caucasian (74.3%), with a median (IQR) age of 61 years (51–70). Subspeciation was performed for 22 isolates with predominant M. abscessus subspecies (77.3%). Moreover, coinfection with other NTM species was present in 28.6% of cases where Mycobacterium avium complex was present in 8 cultures. Sixty-eight percent of the MABC isolates were confirmed to be macrolide resistance; half (12/24, 50.0%) were evident by the presence of functional erm gene, while the other half by antimicrobial susceptibility (Table 3). Of the remaining isolates, 14% were macrolide-susceptible, while no information was reported in 17%. The median (IQR) treatment duration of OMC was 8 months (3.9 – 15.7). The most commonly co-administered antibiotics were intravenous amikacin, imipenem/cilastatin, inhaled amikacin and clofazimine with the same percentage (42.9%) (Table 1). Overall, MABC clinical success was observed in 71.4%, 89.7%, and 90.9% in 3-, 6- and 12 months, respectively (Table 3). Adverse effects reported in 34.3%. The most common side effects were gastrointestinal intolerance (25.7%) and hepatoxicity (11.4%), which led to drug discontinuation in 22.9%. Conclusion OMC treatment showed clinical success in > 70% of patients with pulmonary MABC including patients with macrolide resistant strains for more than 3 months. However, larger studies are needed to validate the outcomes beyond 12 months. Disclosures Kaylee E. Caniff, PharmD, BCIDP, T2Biosystems: Honoraria Michael J. Rybak, PharmD, PhD, MPH, Abbvie, Melinta, Sionogi, Merck, T2Biosystems: Advisor/Consultant|Abbvie, Melinta, Sionogi, Merck, T2Biosystems: Grant/Research Support|Abbvie, Melinta, Sionogi, Merck, T2Biosystems: Speaker

AbstractBackgroundImmune checkpoint inhibitor (ICI) therapy has led to significant improvement in outcomes for patients with nononcogene‐driven advanced non–small cell lung cancer (NSCLC). The rate of crossover and receipt of postprotocol ICI in frontline trials for advanced NSCLC has not been systematically evaluated.MethodsClinicalTrials.gov was used to identify phase 3 studies evaluating the use of immunotherapy or combination chemoimmunotherapy against chemotherapy alone in the frontline management of advanced NSCLC. Data on outcomes, rate of crossover and/or subsequent post‐protocol receipt of immunotherapy, and the start dates of these clinical trials were then extracted.ResultsTwenty‐three frontline trials in nononcogene‐driven advanced NSCLC were identified. Six trials with ICI monotherapy/dual ICI therapy and 17 trials evaluating chemotherapy/ICI in first‐line advanced NSCLC were included in the analysis. The crossover rate ranged 0% to 54% in ICI monotherapy/dual ICI trials and 0% to 52% in chemotherapy/ICI trials. Nineteen of 23 trials provided information on subsequent postprotocol therapies. Among the trials not allowing crossover, postprotocol ICI was administered to 17% to 45.8% of patients. Information regarding the eventual receipt of ICI therapy was available for 22 of 23 trials. Of 6631 patients, 2507 (37.8%) randomized to the control arm eventually received ICI therapy.ConclusionThe rate of crossover and postprotocol ICI use was low in frontline trials for first‐line NSCLC incorporating ICI. Given the proven improved overall survival of ICI in a broad population, there is a need to ensure availability of this life‐prolonging therapy in future trials, either by crossover treatment or postprotocol administration.

ABSTRACT Infections due to nontuberculous mycobacteria (NTM) continue to increase in prevalence, leading to problematic clinical outcomes. Omadacycline (OMC) is an aminomethylcycline antibiotic with FDA orphan drug and fast-track designations for pulmonary NTM infections, including Mycobacteroides abscessus (MAB). This multicenter retrospective study across 16 U.S. medical institutions from January 2020 to March 2023 examined the long-term clinical success, safety, and tolerability of OMC for NTM infections. The cohort included patients aged ≥18 yr, who were clinically evaluable, and` had been treated with OMC for ≥3 mo without a previous diagnosis of cystic fibrosis. The primary outcome was 3 mo clinical success, with secondary outcomes including clinical improvement and mortality at 6- and 12 mo, persistence or reemergence of infection, adverse effects, and reasons for OMC utilization. Seventy-five patients were included in this analysis. Most patients were female (48/75, 64.0%) or Caucasian (58/75, 77.3%), with a median (IQR) age of 59 yr (49–67). Most had NTM pulmonary disease (33/75, 44.0%), skin and soft tissue disease (19/75, 25.3%), or osteomyelitis (10/75, 13.3%), and Mycobacterium abscessus (60/75, 80%) was the most commonly isolated NTM pathogen. The median (IQR) treatment duration was 6 mo ( 4 – 14 ), and the most commonly co-administered antibiotic was azithromycin (33/70, 47.1%). Three-month clinical success was observed in 80.0% (60/75) of patients, and AEs attributable to OMC occurred in 32.0% (24/75) of patients, leading to drug discontinuation in 9.3% (7/75).

Importance Although cancer-related mortality continues to decline, lung cancer remains the No. 1 cause of cancer deaths in the US. Almost half of the patients with non–small cell lung cancer (NSCLC) are diagnosed with early-stage, local or regional disease and are at high risk of recurrence within 5 years of diagnosis. Observations Immune checkpoint inhibitors (ICIs) have improved outcomes for patients with metastatic NSCLC and have recently been tested in multiple clinical trials to determine their efficacy in the neoadjuvant or adjuvant setting for patients with local or regional disease. The landscape for perioperative ICIs in lung cancer is evolving rapidly, with recently reported and soon to mature clinical trials; however, the recent data highlight the potential of ICIs to increase response rates and decrease rates of relapse in early stages of lung cancer. Concurrently, novel applications of cell-free DNA may guide perioperative management strategies. Conclusions and Relevance This article reviews the various approaches of incorporating perioperative use of immunotherapeutic agents for the treatment of early stages of NSCLC.

125 Background: The advent of immunotherapy (IO) has led to significant improvement in outcomes for patients (pts) with advanced non-small cell lung cancer (adv NSCLC). The rate of crossovers and receipt of post-protocol IO in pivotal trials leading to FDA approvals of IO in NSCLC has not been systematically evaluated. Here, we evaluate crossover rates and post protocol therapies for pts with adv NSCLC across multiple first-line (1L) IO monotherapy and chemotherapy/IO (chemo/IO) combination trials. Methods: We utilized the publicly available data from pivotal clinical trials leading to approvals of IO or chemo/IO regimens in 1L treatment of adv NSCLC. We extracted data on outcomes, rate of crossover from control arm to IO, proportion of pts in control arm receiving IO and the start dates of these clinical trials. The primary outcomes were the rates of crossover and the proportion of patients in control arms who received post-control IO. Results: The study included 4 trials with IO monotherapy and 12 trials with chemo/IO combinations in 1L adv NSCLC. The primary endpoints for these trials were PFS (25%), OS (19%), and both PFS and OS (56%). The crossover rate from control arm to experimental arm (with IO) ranged from 0-74% in IO monotherapy trials and 0-49% in chemo/IO trials. Two IO monotherapy trials and five chemo/IO trials did not allow crossover; among them, 3 trials had a PFS/OS co-primary endpoint, while others had OS as primary endpoint. Ten of 16 trials provided explicit information on use of subsequent post-protocol therapies in their publications. Among the two IO monotherapy trials which did not allow crossover, post-protocol IO was administered in only 20-30% of patients. Among the six chemo/IO trials with information on post-protocol therapies, 30%-59% patients on the control arm subsequently received some form of IO on progression. Nine of 12 trials started accrual after 10/2015, when nivolumab was approved in the United States as second-line (2L) therapy for adv NSCLC regardless of tumor PD-L1 expression. Conclusions: Despite the highly significant OS benefit from 2L IO, which was the standard of care (SOC) in the United States, the rates of crossover and post-protocol IO administration was distressingly low in 1L IO monotherapy and chemo/IO trials for 1L adv NSCLC. This low rate of 2L treatment with IO may have been due to limited global availability prior to widespread regulatory approval during the conduct of these trials. There is an increased need for consistency in reporting of crossover treatment and post-protocol treatments to allow adequate assessment of the true 1L benefit with IO. Control arms in pivotal trials require scrutiny to ensure confirmation with SOC to provide access to optimal treatments for patients and prevent magnification of observed benefits in experimental arms. The difficulty lies in the global conduct of large randomized clinical trials with differing regulatory approvals.

This JAMA Oncology Patient Page describes the use of systemic therapy in addition to surgery in the treatment of early-stage lung cancer.

Abstract Background Nontuberculous mycobacteria (NTM) are resistant to numerous antibiotics and lead to significant morbidity and mortality. Omadacycline (OMC) is an aminomethylcycline antibiotic that is Food and Drug Administration-approved for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Furthermore, OMC has shown in vitro activity against NTM. Given that real-world evidence is lacking, our primary objective was to evaluate the clinical success and tolerability of OMC when used for a variety of NTM infections. Methods This was a multicenter, retrospective, observational study conducted from January 2020 to June 2021. We included all patients ≥ 18 years of age that received OMC of any indication for Mycobacterium spp. The primary outcome was clinical success, defined as a lack of all-cause mortality, lack of persistence or re-emergence of infection during or after therapy, and lack of alteration of OMC. Incidence of adverse effects potentially attributable to OMC and reasons for OMC utilization were also analyzed. Results A total of 31 patients were included from 12 geographically distinct academic health systems (median age: 57 (IQR, 45-63) years; 45% male; 81% Caucasian). The majority of isolated pathogens were Mycobacterium abscessus complex (84%) and of those with subspeciation performed (54%), the majority (86%) were subsp. abscessus. The primary infections were of pulmonary origin (67%) and the median (IQR) duration of OMC therapy was 5.3 (3.2-9.4) months. Most isolates did not have OMC susceptibility conducted (87%), while the majority did for tigecycline (90%). Clinical success was reported in 81% of the population. Most patients were on combination antimicrobial therapy, and 39% of patients reported an adverse effect while on OMC (58% gastrointestinal distress). The majority of patients were prescribed OMC due to ease of administration (61%) and antimicrobial resistance to previous antibiotics (42%). Conclusion OMC may be a potential option for the therapy of NTM infections. Prospective, randomized clinical trials are needed to confirm our preliminary findings. Disclosures Julie V. Philley, MD, Paratek Pharmaceuticals (Advisor or Review Panel member)Paratek Pharmaceuticals, Inc. (Consultant) Michael P. Veve, Pharm.D., Cumberland (Grant/Research Support)Paratek Pharmaceuticals (Research Grant or Support) Michael J. Rybak, PharmD, MPH, PhD, Paratek Pharmaceuticals (Research Grant or Support)

Abstract Twelve patients were treated with omadacycline (OMC) as part of a multidrug regimen for Mycobacterium abscessus. The majority of infections were of pulmonary origin (7/12; 58.3%). The median (interquartile range) duration of OMC was 6.2 (4.2–11.0) months. Clinical success occurred in 9/12 (75.0%) patients. Three patients experienced a possible adverse effect while on therapy.

Abstract Background Omadacycline (OMC) is an aminomethylcycline antibiotic in the tetracycline class that has been Food and Drug Administration-approved for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. OMC has been shown to have potent in vitro activity against a broad-spectrum of Gram-positive and Gram-negative organisms, as well as Nontuberculous Mycobacteria (NTM). Due to it’s unique activity and availability as an oral agent, off-label use of OMC has been increasing. We evaluated the real-world effectiveness and safety of OMC for a variety of infections. Methods This was a multicenter, retrospective, observational study that was conducted from January 2020 to June 2020. We included all patients ≥ 18 years of age that received OMC for ≥ 72 hours for any indication and/or pathogen. The primary outcome was clinical success, defined as a lack of 30-day (non-NTM) or 90-day (NTM) mortality or microbiologic recurrence and absence of therapy escalation or alteration. Reasons for OMC utilization and incidence of potential adverse effects attributable to OMC were also analyzed. Results A total of 18 patients were included from six geographically distinct academic health systems (median age: 56 (IQR, 49-60.5) years; 61% male; 72% Caucasian). The majority of OMC use was in NTM (61%; 100% Mycobacterium abscessus) and in Acinetobacter baumannii (22%) for bone/joint (39%) and respiratory tract (33%) infections. OMC was used primarily in the outpatient setting alone (83%) and most isolates did not have OMC susceptibility conducted (89%). Clinical success was reported in 83% of the total population (71% non-NTM and 91% NTM). The majority of patients were prescribed OMC due to antimicrobial resistance to previous antibiotic(s) (61%) and/or due to OMC’s availability as an oral agent (44%). Three patients experienced side effects while on therapy (serum creatinine elevation, AST/ALT increase, and gastrointestinal distress). Conclusion OMC appears to be effective and well-tolerated for a variety of infections caused by various pathogens, including M. abscessus and A. baumannii. Disclosures Michael J. Rybak, PharmD, MPH, PhD, Paratek (Grant/Research Support)

e20502 Background: The CNS is often a site of first disease progression in CRZ-treated ALK+ NSCLC. The ALTA trial is assessing BRG, an investigational next-generation ALK inhibitor, in pts with CRZ-refractory advanced ALK+ NSCLC, including pts with baseline brain metastases. Methods: In ALTA (NCT02094573), pts were stratified by presence of baseline brain metastases and best response to prior CRZ and randomized 1:1 to receive BRG at 90 mg qd (arm A) or 180 mg qd with a 7-d lead-in at 90 mg (arm B). Here, we show data for pts with baseline brain metastases. An independent review committee (IRC) assessed intracranial efficacy. Results: Of 222 pts (112 in arm A; 110 in arm B), 80 (71%)/74 (67%) in A/B had baseline brain metastases per investigators, with median age 49/55 y; 74%/76% had received chemotherapy. As of May 31, 2016, 51%/59% of these pts continued to receive BRG in A/B; median follow-up was 9.6/11.4 mo. Intracranial efficacy is shown in the table. Among these pts, most common treatment-emergent adverse events were: nausea 35%/46% (A/B), headache 30%/31%, vomiting 29%/31%, diarrhea 21%/38%, cough 25%/32%; grade ≥3: increased blood CPK 1%/12%, hypertension 4%/7%, increased lipase 4%/3%. Conclusions: BRG yielded substantial intracranial responses with robust iPFS and acceptable safety in ALK+ NSCLC pts with baseline brain metastases in ALTA. 180 mg (with lead-in) showed consistently improved intracranial efficacy compared with 90 mg. Clinical trial information: NCT02094573. [Table: see text]