Small cell lung cancer (SCLC) is a common lung cancer which presents with extensive stage disease at time of diagnosis in two-thirds of patients. For treatment of advanced disease, traditional ...platinum doublet chemotherapy induces response rates up to 80% but with few durable responses. CPI-613 is a novel anti-cancer agent that selectively inhibits the altered form of mitochondrial energy metabolism in tumor cells.
We evaluated CPI-613 with a single-arm, open-label phase II study in patients with relapsed or refractory SCLC. CPI-613 was given at a dose of 3,000 mg/m2 on days 1 and 4 of weeks 1-3 of 4 week cycle. The primary outcome was response rate as assessed by CT imaging using RECIST v1.1 criteria. Secondary outcomes were progression-free survival (PFS), overall survival (OS), and toxicity. Twelve patients were accrued (median age 57yo) who had previously received between 1 and 4 lines of chemotherapy (median 1) for SCLC with a treatment-free interval of less than 60 days in 9 of the 12 patients.
No complete or partial responses were seen. Ten patients (83%) progressed as best response and 2 (17%) were not evaluable for response. Median time to progression was 1.7 months (range 0.7 to 1.8 months). Eleven patients (92%) died with median overall survival of 4.3 months (range 1.2 to 18.2 months). The study was closed early due to lack of efficacy. Of note, three out of three patients who progressed after CPI-613 and were subsequently treated with standard topotecan then demonstrated treatment response with survival for 18.2, 7.4, and 5.1 months. We conducted laboratory studies which found synergy in-vitro for CPI-613 with topotecan.
Single agent CPI-613 had no efficacy in this study. Further study of CPI 613 in combination with a topoisomerase inhibitor is warranted.
Up to 40% of lung cancer patients develop brain metastasis, and the median survival of these patients remains less than 6 months. Smoking is associated with lung cancer. However, how smoking impacts ...the development of brain metastasis remains elusive. We examined 281 lung cancer patients with distant metastasis and found that smokers exhibited a significantly high incidence of brain metastasis. We found that nicotine enhanced brain metastasis, while a depletion of microglia suppressed this effect in vivo. Nicotine skewed the polarity of microglia to the M2 phenotype, thereby increasing the secretion of IGF-1 and CCL20, which promoted tumor progression and stemness. Importantly, nicotine enhanced the expression of SIRPα in microglia and restricted their phagocytic ability. We also identified a compound, parthenolide, that suppressed brain metastasis by blocking M2 polarization. Our results indicate that nicotine promotes brain metastasis by skewing the polarity of M2 microglia, which enhances metastatic tumor growth. Our results also highlight a potential risk of using nicotine for tobacco cessation.
This study describes patients' prognostic awareness and palliative care use in the setting of immunotherapy for metastatic non-small cell lung cancer (mNSCLC).
We surveyed 60 mNSCLC patients ...receiving immunotherapy at a large academic medical center; conducted follow-up interviews with 12 survey participants; and abstracted palliative care use, advance directive completion, and death within a year of survey completion from the medical record.
Forty seven percent of patients surveyed thought they would be cured; 83% were not interested in palliative care. Interviews suggested oncologists emphasized therapeutic options when discussing prognosis and that commonly used descriptions of palliative care may exacerbate misperceptions. Only 7% had received outpatient palliative care and 8% had an advance directive a year after the survey; only 16% of the 19 patients who died had received outpatient palliative care.
Interventions are needed to facilitate prognostic discussions and outpatient palliative care during immunotherapy. Clinical Trial Registration Number NCT03741868.
Neurological adverse events (NAEs) are infrequent immune checkpoint inhibitor (ICI) outcomes poorly characterized in extant research, complicating their clinical management.
This study characterized ...the frequency, severity, patterning and timing of NAEs using a large retrospective registry, including all patients who received at least one dose of an ICI from 2/1/2011-4/7/2022 within our health network.
Among 3137 patients, there were 54 NAEs (1.72% any grade; 0.8% grade 3-4). Most NAEs were peripheral (57.4%) versus central (42.6%). Melanoma and renal cell carcinoma were significantly associated with NAEs.
The incidence of NAEs was rare though higher than many prior case estimates; the timing was consistent with other AEs. NAEs frequently occurred in tumor types known to favor brain metastases.
Background
The efficacy of just-in-time teaching (JiTT) screencasts for graduate medical education on an inpatient adult hematology-oncology service (HOS) setting is not known. Our preceding pilot ...data identified six high-yield topics for this setting. The study objective was to evaluate screencast educational efficacy.
Methods
Internal medicine residents scheduled to start a rotation on the primary HOS of an academic medical center were eligible for this parallel, unblinded, randomized controlled trial with concealed allocation. Participants underwent block randomization to the usual educational curriculum either with or without access to a series of novel screencasts; all participants received an anonymous online end-of-rotation survey and a $20 gift certificate upon completion. The primary outcome was the change in attitude among learners, measured as their self-reported confidence for managing the clinical topics.
Results
From 12/9/2019 through 6/15/2020, accrual was completed with 67 of 78 eligible residents (86%) enrolled and randomized. Analysis was by intention-to-treat and participant response rate was 91%. Sixty-four percent of residents in the treatment arm rated their clinical management comfort level as “comfortable” or “very comfortable” versus 21% of residents in the usual education arm (
p
= 0.001), estimated difference = 43% (95% CI: 21–66%), using a prespecified cumulative cutoff score. Treatment arm participants reported that the screencasts improved medical oncology knowledge base (100%), would improve their care for cancer patients (92%), and had an enjoyable format (96%).
Conclusion
Residents on a busy inpatient HOS found that a JiTT screencast increased clinical comfort level in the management of HOS-specific patient problems.
: While frailty is a well-established predictor of overall mortality among patients with metastatic non-small cell lung cancer (mNSCLC), its association with patient-reported outcomes is not ...well-characterized. The goal of this study was to examine the association between an electronic frailty index (eFI) score and patient-reported outcome measures along with prognostic awareness among patients with mNSCLC receiving immunotherapy.
: In a cross-sectional study, patients with mNSCLC who were on immunotherapy completed the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) and the National Cancer Institute Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). We utilized bivariate analyses to compare quality of life, symptoms, supportive services, and prognostic awareness among 3 groups defined by e-frailty status.
: Sixty patients (mean age 62.5 years, 75% Caucasian, 60% women) participated. Most patients were pre-frail (68%), with 13% being frail and 18% non-frail. Pre-frail and frail patients had significantly lower physical function scores (mean 83.9 fit vs 74.8 pre-frail vs 60.0 frail,
= .04) and higher rates of self-reported pain (75% frail vs 41.5% pre-frail vs 18.2% fit;
= .04) compared to non-frail patients. We found no differences in palliative referral rates.
: Pre-frail and frail mNSCLC patients identified by the eFI have higher rates of pain and physical functional impairments than non-frail patients. These findings highlight the importance of emphasizing preventive interventions targeting social needs, functional limitations, and pain management, especially among pre-frail patients to reduce further decline.
Immunotherapy and chemoimmunotherapy clinical trials for metastatic non–small-cell lung cancer (mNSCLC) have generally excluded patients with poor performance status (PS) and have utilized ...patient-reported measures that could miss some symptoms associated with immunotherapy. The goals of this study were to describe quality of life and symptom burden among mNSCLC patients receiving immunotherapy in clinical practice, and to examine burden by Eastern Cooperative Oncology Group performance status (ECOG PS) and age.
Between 2017 and 2018, mNSCLC patients receiving immuno/chemoimmunotherapy at an academic medical center completed the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) and the National Cancer Institute Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Univariate and bivariate analyses described EORTC-QLQ-C30 subscales and the proportion reporting at least moderate PRO-CTCAE symptoms, and compared scores by ECOG PS (0/1 vs. 2/3) and age (< 70 vs. ≥ 70 years).
Sixty patients (60% female; 75% < 70 years old; 68% ECOG PS 0/1; 57% receiving single-agent immunotherapy) participated. The mean EORTC-QLQ-C30 global health score was 62.6; EORTC symptoms were highest for fatigue, insomnia, dyspnea, and financial concerns (all > 30). Global health and pain were worse in ECOG PS 2/3 patients. For PRO-CTCAE, 20% to 40% reported at least moderate gastrointestinal, respiratory, dermatologic, arthralgia, or myalgia symptoms. The PRO-CTCAE pain score was higher among ECOG PS 2/3 patients.
In clinical practice, global health was largely comparable to published clinical trials, but PRO-CTCAE items indicated a higher symptom prevalence. Closer monitoring of symptoms is warranted in ECOG PS 2/3 patients.
The quality of life and symptom experience for metastatic lung cancer patients treated with immunotherapy or chemoimmunotherapy in routine care has not been described. In our survey of 60 metastatic lung cancer patients receiving these treatments, 20% to 40% reported moderate symptoms (eg, rash, muscle ache). Patient-reported outcomes need to be monitored in clinical practice, especially for patients with worse physical function.
Background
Immune checkpoint inhibitors (ICIs) are a promising class of anticancer drugs associated with immune-related adverse events (IRAEs). In registration studies of selected cancer populations, ...neurologic IRAEs were rare. Post-marketing experience describing their prevalence in clinical practice continues to be reported.
Methods
A retrospective cohort of patients treated at our institution with ICIs from 2005 to 2017 was identified. Patients with new neurologic ICD codes documented during or after ICI treatment were enrolled. Comprehensive medical record review identified patients with neurologic IRAEs causally linked to ICIs. This study focused on CTCAE grade 2–4 IRAEs.
Results
526 patients were screened; 55 candidate patients were identified; 5 cases met criteria for neurologic IRAEs, an incidence of 0.95% (
n
= 5/526). IRAEs identified were transverse myelopathy, demyelinating sensorimotor polyneuropathy, oculomotor nerve palsy, sensory neuropathy, and posterior reversible encephalopathy syndrome. ICIs were held in three patients, rechallenged in one, and dose-reduced in one. Corticosteroids were given in three patients, and response varied from complete symptom resolution to minimal response and ultimately death. Other treatments were based on IRAE presentation, including gabapentin, antihypertensives, and IV immunoglobulin. Patients with combination therapy appeared to suffer more severe IRAEs producing more substantial long-term morbidity and mortality.
Conclusion
In this clinical practice study, the incidence of neurologic IRAEs from ICIs was 0.95%. Although rare, neurologic IRAEs can be highly variable and severe, and patients with combination immunotherapy appeared to suffer more severe IRAEs. Neurologists play an important role in the early identification and management of IRAEs to reduce long-term morbidity and mortality.
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