e24003 Background: Immune checkpoint inhibitors (ICI) can lead to durable responses in some patients with advanced non-small cell lung cancer (NSCLC) with less toxicity than chemotherapy. However, ICI can cause idiosyncratic adverse effects and radiographic responses can be difficult to interpret, making prognostication difficult and potentially impeding a timely transition to hospice. Our purpose was to explore end of life (EOL) outcomes in NSCLC patients treated with ICI. Methods: Retrospective data were collected on all patients with NSCLC started on ICI at single center (2014-2018) and who died before last known follow-up. EOL outcomes included hospitalizations, ICU admissions, timing/location of hospice referral and death. Charts were reviewed to identify barriers to hospice referrals or enrollment. Outcomes were compared to published data of similar cohort (2008-2010) from same institution treated with chemotherapy. Results: Out of 143 patients who died, 83 (58%) had internal hospice referral by cancer center; 15 (11%) were referred by external provider. Hospitalization frequency was associated with higher likelihood of internal hospice referral (p 0.04). Internal hospice referral was not associated with differences in age, sex, race, ethnicity, smoking history, cancer subtype, treatment response/toxicity, or overall survival. Internal hospice referral was associated with decreased rates of death on the hospital floor (p < 0.001) and the intensive care unit (ICU, p < 0.001). When compared to chemotherapy cohort, there was similar rate of hospice referral (68% vs. 74%, p 0.33) but higher rates of starting new systemic therapy within 30 days of death (17% vs. 6%, p 0.001) and last dose within 14 days of death (13% vs. 5%, p 0.005). Other EOL outcomes (hospitalization frequency, death in ICU) were similar, although ICI cohort trended towards a lower rate of death on the floor than chemotherapy cohort (16% vs. 25%, p 0.06). Barriers to hospice referral were not well documented by providers but lack of family support for home EOL care was a common reason patients declined hospice. Conclusions: ICI was associated with a higher rate of systemic treatment at EOL as compared to a historical chemotherapy cohort, although the rates of hospice referral and other outcomes were similar.
Immune-related adverse events (irAEs) are a unique characteristic of immune checkpoint inhibitors (ICIs) and can confer survival benefits. For example, melanoma patients who develop vitiligo as an irAE tend to have improved overall survival (OS), hypothesized to be due to molecular mimicry between similar antigens.1 2 Further analysis of the impact of irAEs on OS among real-world lung cancer patients is needed; this study addresses this need in a hospitalized population.3–5
Methods
This single-center retrospective cohort study collected data on a subset of lung cancer patients who received > 1 dose of an ICI (nivolumab or pembrolizumab) between 6/1/18 and 2/1/20 (n=210) and who were subsequently hospitalized and received > 1 dose of systemic corticosteroids for any indication (n=97). Patients were stratified according to whether or not they developed irAEs at any point. Clinical factors for data collection included: comorbidities, irAE development (organ and grade), cancer stage, ICI cycles, biomarkers, progression, and survival. OS analysis was calculated from the first dose of ICI to date of death or last known follow-up. To assess significance, the log-rank approximation of the chi-square test was used.
Results
Kaplan-Meier survival analysis revealed that patients who developed irAEs (n=28, median OS 14.9 months) did not have an association with increased median OS when compared to patients without irAEs (n=69, 8.7 months, p 0.072) (table 1). The subgroup of patients who developed either colitis or pneumonitis had an increased median OS (n=15, 41.3 months, p 0.049) compared to patients without irAEs . Patients who only experienced grade ≥ 3 irAEs (n = 20, median OS 17.0 months, p 0.095) did not show any OS difference compared to patients without irAEs. Patients who developed ≥2 irAEs of any grade (n = 7, median OS 17.0 months, p 0.22) did not show any OS difference as compared to patients without irAEs.
Conclusions
Initial analysis shows that while generalized irAEs in this hospitalized lung cancer population were not significantly associated with OS change, patients who developed pneumonitis and colitis were associated with treatment response and increased OS. Patients could be developing an interaction between pneumonitis and lung cancer analogous to the interaction between vitiligo and melanoma via molecular mimicry, resulting in improved OS. Thus, certain organ-related irAEs may indicate an immune response to ICIs depending on the malignancy being treated, correlating with improved prognosis.
References
Bertrand A, Kostine M, Barnetche T, Truchetet M-E, Schaeverbeke T. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med 2015;13:211. Teulings H-E, Limpens J, Jansen SN, et al. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol 2015;33(7):773–81. Owen DH, Wei L, Villalona-Calero MA, et al. Impact of immune-related adverse events (irAE) on overall survival (OS) in patients treated with immunotherapy for non-small cell lung cancer (NSCLC). J Clin Orthod 2017;35(15_suppl):9080–9080. Haratani K, Hayashi H, Chiba Y, et al. Association of immune-related adverse events with nivolumab efficacy in non–small-cell lung cancer. JAMA Oncol 2018;4(3):374–8. Owen DH, Wei L, Bertino EM, et al. Incidence, risk factors, and effect on survival of immune-related adverse events in patients with non–small-cell lung cancer. Clin Lung Cancer 2018;19(6):e893–900.
Ethics Approval
The study protocol was approved by Wake Forest Baptist Medical Center9s institutional review board.
Optimal diagnostic algorithm to differentiate checkpoint inhibitor pneumonitis (CIP) from mimics is uncertain; patients with respiratory comorbidities often receive prolonged corticosteroids until diagnostic clarification. Drawbacks to empiric use of corticosteroids include decreased immunotherapy (IO) efficacy and increased infectious risk. This retrospective study systematically collected data on patients treated for lung cancer who were suspected to have severe CIP.
Methods
This single-center retrospective cohort study collected data on all lung cancer patients who received > 1 dose of an immune checkpoint inhibitor between 6/1/18 and 2/1/20 (n=210), were subsequently hospitalized and received > 1 dose of systemic corticosteroids for any indication (n=97). Data were collected on clinical factors including comorbidities, cancer stage, IO cycles, biomarkers, diagnostic work-up, antibiotics, steroids, progression, and survival. A blinded radiologist reviewed all imaging of suspected CIP cases and categorized their radiographic patterns.
Results
In our high-risk cohort of 97 patients, median follow-up was 23 months with progression in 54 patients (56%) at median 11 months and death in 67 patients (69%) at median 14mo. Twelve patients (12%) were suspected to have severe CIP after IO treatment for lung cancer; CIP was confirmed in 5/12 and ruled-out (mimics) in 7/12 after 30 and 3 median IO cycles, respectively. Most suspected patients underwent CXR, CTA chest, blood cultures, and received empiric antibiotics. Common radiographic patterns were ground-glass opacities, organizing pneumonia, hypersensitivity pneumonitis, and acute interstitial pneumonia/acute respiratory distress syndrome (AIP/ARDS) among confirmed cases (4/5) and ground-glass opacities, organizing pneumonias, bronchiolitis, AIP/ARDS among mimics (4/7). The median time to confirm CIP or rule out a mimic was 5 ± 4 days. Median time to onset of symptoms differed substantially for confirmed and mimic cases: 17 months and 1 month, respectively.
Conclusions
CIP mimics were more common than confirmed cases in routine clinical practice, particularly among patients hospitalized for respiratory symptoms <1 month after initiating immunotherapy for lung cancers. In these cases, it is reasonable to empirically cover possible CIP with shorter (~1 week) courses of steroids until diagnostic clarity is achieved. CT imaging should be obtained as it is sensitive though not specific for CIP. CIP mimics may contribute to the higher incidence of CIP reported by real-world patient registries than by clinical trials.
Ethics Approval
The study was approved by Wake Forest Baptist Medical Center's Ethics Board, IRB approval number 00044126
e21151 Background: Although predictive of chemotherapy toxicity, geriatric assessment measures are not systematically collected in clinical practice and may or may not be predictive for immune-related adverse events. Furthermore, hospitalization during immune checkpoint inhibitor (ICI) treatment for advanced lung cancer has variable prognostic significance. This study aimed to evaluate whether age and documented patient characteristics mapped to geriatric assessment domains (frailty markers, FM) predict survival in this setting. Methods: A single-center retrospective cohort of advanced stage lung cancer patients who received >1 dose of an ICI from 6/1/18 to 2/1/20, were later hospitalized, and received ≥ 1 dose of systemic corticosteroids (n=97) was analyzed. Chart review ascertained documentation of any of the following FMs prior to ICI initiation: inability to walk one block, unintentional weight loss, decreased social activities, recent falls, need for assistance with medications, visual or hearing impairments, living alone, and concern regarding social support. Patients were stratified according to age and three FM categories (0 FM [low risk], ≥1 FMs [at risk], and ≥2 FMs [high risk]). Overall survival (OS) analysis was calculated from first dose of ICI to date of death or last follow-up. Cox’s proportional hazards models were used to assess the relationship between FMs and age on OS; hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Results: Analysis of < 75 and ≥ 75 yo revealed a median OS of 15.1 and 5.4 months respectively (HR 2.76, CI 1.62-4.72). Controlled for performance status (PS), older age (≥75 yo) was associated with a higher risk of death (HR 2.39, CI 1.32-4.31). FMs were associated with higher mortality, adjusted for PS and age (at risk patients HR 1.81, CI 1.03-3.16; high risk patients HR 2.02, CI 1.07-3.78). PS prior to starting ICI was not associated with OS. Conclusions: Age ≥ 75 yo is associated with short survival among lung cancer patients hospitalized while receiving ICI. Pre-treatment FMs documented as part of usual care were associated with worse OS, even after controlling for PS and age. This study shows promise for use of machine learning algorithms to stratify risk in hospitalized patients undergoing treatment for lung cancer with ICIs. These data would allow providers to better target serious illness conversations and end-of-life resources.[Table: see text]
e20094 Background: There are limited effective treatment options for rrSCLC. Based on results from CheckMate 032 (n = 98) and KEYNOTE-158 (n = 107), both of which were limited to performance status (PS) 0-1, guidelines recommend consideration of single agent PD-1 immunotherapy (IO) for patients (pts) with PS 0-2. Methods: All rrSCLC pts receiving single agent IO at our institution from May 2016 – April 2018 were retrospectively analyzed with IRB approval. Primary endpoints were overall survival (OS) and end-of-life outcomes. Results: 48 rrSCLC pts who were predominantly PS 2-3 (56%), female (63%), and Caucasian (90%) received single agent IO with either nivolumab (94%) or pembrolizumab (6%) for either relapsed (81%) or refractory (19%; defined as initial diagnosis < 180 days) SCLC. They received median 3 cycles (IQR 2-5). 32 deaths occurred during the analysis period. 6 and 12 month (mo) OS were 31% and 18%, as compared to 45% and 33% reported in CheckMate, respectively. Adverse events (AEs) leading to treatment discontinuation occurred in 5 (10%) and serious AEs (pneumonitis and posterior reversible encephalopathy syndrome) occurred in 2 (4%). For end-of-life outcomes, 18 (38%) were referred to hospice at any point, 8 (17%) began IO within 30 days of death, and 7 (15%) received a dose of IO within 14 days of death. The subgroup of pts who received ≥2 prior lines of therapy appear to have had greater benefit. Conclusions: Although tolerable, salvage single agent IO for rrSCLC in these unselected pts had poor efficacy and may have led to under-utilization of end-of-life resources. It may still be beneficial among pts with more indolent, treatment-responsive disease, as indicated by multiple lines of prior therapy. But overall, these results support the combination of IO with chemotherapy or novel agent as part of a clinical trial. Further investigation is warranted to better define its use in this setting. [Table: see text]
Lymphangitic carcinomatosis is a difficult to treat disease entity and usually portends a poor prognosis given the advanced state in which it is often diagnosed. Treatment is usually based on standard therapy of the primary malignancy, but in most cases, is palliative in nature. This case highlights the potential for PD-1 immunotherapy as both a rapid and durable treatment for lymphangitic carcinomatosis.
A 26-year-old man with history of extensive tophaceous gout presented to the referring facility with decreased bilateral lower extremity sensation and motor function that began acutely 1 week prior to admission and had progressed to urinary incontinence. The patient was admitted to the intensive care unit due to concern for sepsis secondary to epidural abscess. The patient was started on empiric vancomycin and cefepime. Neurosurgery did not recommend acute neurosurgical intervention given the lack of a compressive lesion. Aspiration of the paraspinal collection by interventional radiology subsequently showed crystals consistent with tophaceous gout. Given the high initial suspicion for gout and results of the paraspinal aspiration, the patient was started on prolonged steroid taper as well as allopurinol and colchicine. The patient eventually had partial neurological recovery with discharge to an inpatient rehabilitation facility for further physical therapy rehabilitation.
