Immunotherapy Therapy Research Articles

Efficacy of immunotherapy retreatment in patients with non-small cell lung cancer receiving consolidative durvalumab.

8625 Background: The standard of care for patients with stage III, unresectable non-small cell lung cancer (NSCLC) is curative intent chemoradiation followed by durvalumab consolidation. However, most patients progress necessitating further treatment. Although immunotherapy (IO) is the cornerstone of treatment in advanced/metastatic disease, the benefit in patients who received prior durvalumab is unclear. Clinical trials excluded prior IO exposure and current guidelines do not provide specific recommendations. This study aims to characterize the efficacy of post-durvalumab IO treatment. Methods: This was a retrospective cohort study conducted at the University of North Carolina (UNC) Medical Center. Adult patients with unresectable NSCLC who received chemoradiation and consolidative durvalumab followed by subsequent systemic therapy for disease progression between February 2018 to May 2023 were included. Patients were excluded if they received targeted therapy as subsequent systemic treatment. The primary endpoint was real-world progression-free survival (rwPFS) of post-durvalumab treatment. Key secondary outcomes included physician assessed response, overall survival (OS), and subgroup analyses to identify biomarkers which may predict benefit from IO retreatment. Results: A total of 66 patients met inclusion criteria, of which 39 (59%) received subsequent chemotherapy alone and 27 (41%) received IO-containing therapy. Of those who received IO-containing treatments, 18 received chemotherapy plus IO (chemoIO) and 9 received IO alone. Durvalumab was discontinued for therapy completion (chemotherapy: 18%, IO: 26%), disease progression (chemotherapy: 54%, IO: 48%), or side effects (chemotherapy: 26%, IO: 19%). No significant difference was observed between median rwPFS of chemotherapy versus IO-containing therapy (7.0 months vs 5.8 months, respectively; p = 0.9419) or OS (13.0 months vs 12.6 months, respectively; p = 0.5769). Notably, patients in our cohort who received IO alone had a numerically longer rwPFS compared to chemoIO (12.6 months vs 5.8 months, respectively; p = 0.3951), as well as a numerically longer OS (12.6 months vs 6.4 months, respectively; p = 0.8885). Conclusions: This study found that there were no statistically significant differences in median rwPFS or OS between chemotherapy or IO-based regimens following the conclusion of durvalumab consolidation. Interestingly, we observed a numerically improved rwPFS and OS in those who received IO alone compared to chemoIO, which suggests there may be key clinical or molecular features that may help identify patients who benefit from IO therapy. We acknowledge the limitations of this small, retrospective study. The efficacy of IO-based regimens post-durvalumab warrants further investigation in a larger, prospective manner to assess the risks and benefits of IO retreatment.

Immune response to SARS-CoV-2 vaccine administered to patients with solid cancers under systemic treatment: A prospective, monocentric study (Immunocovid-19).

e23093 Background: Despite vaccination, COVID-19 could still cause severe disease in immunocompromised patients (pts). While subsequent vaccine doses increase immune response in the general population, few data concerning cancer pts under systemic treatment are reported. Methods: This study will be conducted on blood samples from 1000 pts admitted to Reggio Emilia AUSL-IRCCS Cancer Center and undergoing systemic therapies who received ≥ 2 vaccine doses. The samples will be analyzed at Clinical Microbiology and Chemistry Laboratories of Reggio Emilia AUSL-IRCCS. We will perform antibody IgM-IgG serology by means of COVID-19 VIRCLIA® Monotest and anti-spike antibodies evaluation using LIAISON® SARS CoV-2 Trimerics IgG. We will also investigate cell immune response (B and T lymphocyte counts) and analyze specific lymphocyte subsets on the first 200 pts treated with chemo- (CT) or immunotherapy (IO). Then, we will evaluate the T-cell response on the first 50 pts and those with an inadequate anti-spike serologic response through the T-SPOT.COVID test. Statistical analyses will be conducted by the Clinical Studies and Statistical Unit Staff. Results: Here, we report preliminary data on the first 240 pts enrolled and treated with CT (55.4%), IO (26.3%), or other therapies (18.3%). Most of the pts were male (58%), had metastatic cancer (82%), and no previous COVID-19 infection (60%). 84% of pts were affected by gastrointestinal, lung, urogenital and breast cancer. We stratified pts in three groups according to the time from the last vaccine dose (0-6/6-12/ > 12 months). We showed no significant decrease in cellular and humoral immune response over time from the last vaccine dose, independent of the specific treatment received, also if CT (Table 1). Furthermore, clinical characteristics as gender, treatment, and primary tumor site appear not to influence immune response, even if a trend to a higher response in pts previously affected by COVID-19 has been observed. The T-SPOT.COVID test performed on the first 27 pts showed that 19% had no T-cell activation, even with good IgG response. Conclusions: This feasible and cost-effective study has a potential impact on public health. Although these are preliminary data, the immune response to COVID-19 vaccines remains good after 12 months from the last dose administered in cancer pts. The enrollment is ongoing, and we could provide relevant information on the influence of clinical factors on the immune response and identify specific subgroups that could benefit from different vaccine approaches. [Table: see text]

Real-world outcomes of patients with resected stage III melanoma treated with adjuvant therapies.

Both immunotherapy (IO) and targeted therapy (TT) are used as adjuvant (adj) treatment for stage III melanoma, however, data describing real-world outcomes are limited. In addition, a significant proportion of patients relapse, for whom best management is unclear. The aim of our study was to assess the efficacy, and safety of adj anti-PD1 IO and TT in a real-world cohort of patients with resected stage III melanoma, and further delineate patterns of recurrence and treatment strategies. We retrospectively analyzed 130 patients who received adj therapy (100 anti-PD1 IO and 30 TT). At a median follow-up of 30 months, median relapse-free survival (RFS) was 24.6 (95% CI, 17-not reached [NR]) versus 64 (95% CI, 29.5-NR) months for the TT and IO groups, respectively (p = 0.26). Median overall survival (OS) was NR for either subgroup. At data cutoff, 77% and 82% of patients in TT and IO arms were alive. A higher number of grade ≥3 treatment-related adverse events (AEs) were noted in the IO group (11% vs. 3%), however, a higher proportion of patients permanently discontinued adj therapy in the TT group (43% vs. 11%) due to toxicity. Strategies at relapse and outcomes were variable based on location and timing of recurrence. A significant number of patients who relapsed after adj IO received a second round of IO. Among them, patients who were off adj IO at relapse had superior second median RFS (mRFS2), compared to those who relapsed while on adj IO; mRFS2 was NR versus 5.1 months (95% CI, 2.5-NR), respectively, p = 0.02. In summary, both TT and IO yielded prolonged RFS in a real-world setting, however, longer follow-up is needed to determine any potential OS benefit. Adj therapy, particularly TT, may not be as well tolerated as suggested in clinical trials, with lower completion rates (59% vs. 74%) in a real-life setting. Overall, patients who relapse during adj therapy have poor outcomes, while patients who relapse after discontinuation of adj IO therapy appear to benefit from IO re-treatment.

Abstract 1207: Immune subtyping identifies a subset of HR+HER2- early-stage breast cancer patients with a very high likelihood of response to neoadjuvant immunotherapy (IO): Results from 5 IO arms of the I-SPY2 TRIAL

Abstract Background: Neoadjuvant immunotherapy (IO) has become standard of care for early-stage triple negative breast cancer (TNBC). I-SPY2 was the first randomized trial to examine the efficacy of IO therapy in high-risk HR+HER2- breast cancer, where most IO arms showed improved efficacy relative to control. We also previously showed immune-gene expression signatures associate with pathologic complete response (pCR) in HR+HER2- treated with IO; and developed a clinically applicable Immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the Response Predictive Subtypes. Here we report the performance of ImPrint in HR+HER2- patients from 5 IO arms. Methods: 204 HR+HER2- (MammaPrint high risk) patients from 5 IO arms (anti-PD1, anti-PDL1/PARPi, anti-PD1/TLR9 dual-IO, and anti-PD1 +/- LAG3 dual-IO) and 191 patients from the control arm were included in this analysis. Patients were classified ImPrint+ (likely sensitive) vs. ImPrint- (likely resistant), by Agendia, Inc, using pre-treatment mRNA. Performance of ImPrint for predicting pCR to IO was characterized and compared to that of MammaPrint (ultra) High2 risk (MP2) and tumor grade (III). Based on the DRFS of pCR vs. non-pCR HR+HER2-/ImPrint+ patients (median follow up ~4.5yr), we predicted the DRFS in the IO vs. control arms using an exponential model as a function of the pCR rates. Results: Overall, the pCR rate over the 5 IO arms was 33%. 28% of HR+HER2- patients were ImPrint+; and pCR rates with IO were 76% in ImPrint+ vs. 16% in ImPrint-, with the highest pCR rate >90% in a dual-IO arm. In the control arm, pCR rates were 33% in ImPrint+ and 8% in ImPrint-. Based on the pCR rates in the IO vs. control (76% vs. 33%), the predicted DRFS of HR+HER2-/ImPrint+ patients are 91% vs 80% at 5 years, respectively. This translates to a risk reduction of 52% for the IO arm relative to standard chemotherapy in HR+HER2-/ImPrint+ patients. We also compared MP2 and tumor grade (III) to ImPrint+ as pCR predictors, as these markers have been used or proposed as selection markers for neoadjuvant IO trials in HR+HER2-. The pCR rates for MP2, Grade III, at 56%, 45%, respectively, are much smaller than that for ImPrint+ at 75% pCR; thus ImPrint appears to be a more precise predictive biomarker for neoadjuvant IO therapy in the HR+HER2- breast cancers. Conclusion: These results suggest that a subset of high risk HR+HER2- breast cancers is highly sensitive to immunotherapy, and by using a specific and sensitive selection strategy patients could achieve pCR rates similar to what is seen with best neoadjuvant therapies in TNBC and HER2+ (i.e., pCR rate > 65-70%). ImPrint, an FDA IDE-enabled assay currently being further evaluated in I-SPY2, may represent the way to identify patients for IO that best balances likely benefit vs risk of serious immune-related adverse events. Citation Format: Denise M. Wolf, Christina Yau, Lajos Pusztai, Rita Nanda, Jo Chien, Erica Stringer-Reasor, Rebecca Shatsky, Claudine Isaacs, MInetta Liu, Hyo Han, Hatem Soliman, Michael Campbell, Annuska Glas, Andrei Barcaru, Lorenza Mittempergher, Midas Kuilman, Lamorna Brown Swigart, Gillian Hirst, Hongmei Yu, Philip Beineke, Amrita Basu, I-SPY2 Investigators, Douglas Yee, W. Fraser Symmans, Angela DeMichele, Jane Perlmutter, Amy Delson, Laura Huppert, Hope Rugo, Amy Clark, Nola Hylton, Paula Pohlmann, Laura Esserman, Laura van 't Veer. Immune subtyping identifies a subset of HR+HER2- early-stage breast cancer patients with a very high likelihood of response to neoadjuvant immunotherapy (IO): Results from 5 IO arms of the I-SPY2 TRIAL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1207.

Abstract 5667: Intratumoral heterogeneity in gastric cancer related with survival and tumor microenvironment

Abstract Gastric cancer (GC), often diagnosed at an advanced stage, poses a significant therapeutic challenge due to its resistance to treatment. The understanding of intratumoral heterogeneity, crucial for tumor cell survival, remains limited in GC. We conducted a comprehensive analysis of three patient groups (intraperitoneal metastasis [IM], hematogenous metastasis [HM], and both metastasis [HIM]) undergoing immunotherapy (IO) and chemotherapy. Utilizing single-cell RNA sequencing and TCR sequencing, we examined 11 adjacent normal, 10 HM, 8 IM, and 5 HIM primary GC samples. In epithelial cells, three distinct tumor clusters (Tumor_1, Tumor_2, and Tumor_3) were identified. Trajectory analysis revealed the differentiation of chief cells into Tumor_1, subsequently dividing into more malignant cell types, Tumor_2 and Tumor_3. Tumor_2 was enriched in IM, while Tumor_1 was enriched in HM and HIM. Patients grouped by Tumor_1, 2, 3 levels showed varying survival outcomes. Surprisingly, high Tumor_2 levels correlated with increased survival, attributed to elevated HLA and PDL1 expression, promoting immune cell recruitment and robust response to IO therapy. Conversely, Tumor_3 high patients exhibited worse survival, with enrichment in metabolic pathways associated with glycolysis and hypoxia, linking to metastasis. We observed the proportion of T cells that increased presence of CD8 effector cells among patients exhibiting high levels of Tumor_1 and Tumor_2. Through TCR analysis, we found heightened clonality in both CD8 effector cells and exhausted T cells in patients with elevated Tumor_1 and Tumor_2 levels. This suggests that the activated CD8 effector T cells in these patients may enhance their ability to effectively target and attack cancer cells. In summary, this study provides a comprehensive picture of intratumoral heterogeneity in GC can impact the survival and tumor microenvironment. The unexpected high survival in Tumor_2 patients emphasizes the potential of targeting specific pathways for improved therapeutic outcomes. Additionally, the observed T cell dynamics and clonality in Tumor_1 and 2 underscore the importance of understanding the immune microenvironment for effective cancer attack. Citation Format: Do-eon Gu, Woo Sun Kwon, Sun Young Rha, Woong-Yang Park. Intratumoral heterogeneity in gastric cancer related with survival and tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5667.

Immunotherapy-Associated Immune Thrombocytopenia: Treatment Paradigms

Introduction: Immune cytopenias are a rare but potentially serious complication of immunotherapy (IO) used in the treatment of cancer. Immunotherapy-associated Immune Thrombocytopenia (IO-ITP) is a diagnosis of exclusion and often under recognized in the setting of cancer-directed multidrug regimens. In general it is managed with interruption of IO and disease-specific therapies based on management of the corresponding primary hematologic disorder. Our goal was to identify and characterize IO-ITP and to compare treatment approaches with primary immune thrombocytopenia (p-ITP). Methods: Data was obtained from TriNetX, a de-identified national health research network with data sourced from 76 health care organizations (HCOs) with over 107 million patients located in the United States. We identified all adults (≥18 years) with diagnosis of ITP (ICD-10: D69.3) between 2015-2023. We categorized patients into two cohorts: IO-ITP, those with a diagnosis of ITP after IO use (pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, ipilimumab) and a diagnosis of neoplasm (ICD-10: C00-D49); and p-ITP: those with ITP without neoplasm nor IO use. For both cohorts, we collected demographic, laboratory and treatment characteristics. To compare treatment approaches, we subcategorized cohorts by platelet count to identify patients who would qualify for ITP-directed therapy, using a platelet count ≤75x10 3/µL in IO-ITP and ≤50x10 3/µL in p-ITP. Platelet count cutoffs were defined based on current guidelines recommendations. We investigated the use of first-line and rescue therapies: glucocorticoids and IVIG; second-line therapies: thrombopoietin agonists (TPO-RAs: romiplostim and eltrombopag) and rituximab; third-line therapies: cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil, bortezomib, avatrombopag and fostamatinib; and splenectomy, based on guidelines for management of p-ITP. For continuous data, we performed independent t-tests and for categorical data, chi-square tests. All tests were two-tailed with alpha level of .05. Results: In total, we identified 241 individuals with IO-ITP and 14,717 with p-ITP. Individuals with IO-ITP had a mean age of 64 years (21-86) and were predominantly male (57.3%), whereas those with p-ITP, were younger, (mean age 48 years,18-89) and predominantly female (63.2%) (Table). Both groups were mostly white and had similar mean platelet counts. Cancer of the respiratory system (40.7%) followed by skin malignancies (26.1%) were the most common subtypes in those with IO-ITP. Pembrolizumab was the IO most frequently used (52.7%). Within first-line and rescue therapies, a higher proportion of patients with IO-ITP required steroids as compared to those with p-ITP (81.4% vs 58.6%, p value <0.001). There was no significant difference between the groups in the utilization of IVIG. With respect to second-line therapies, in IO-ITP, a greater proportion received TPO-RAs (27.9%) compared to rituximab (6%). More patients with p-ITP received rituximab as compared to IO-ITP (14.9% vs 6%, p value < 0.001). Among TPO-RAs, romiplostim was more commonly used in IO-ITP (19.7% vs 10.9%), whereas eltrombopag was preferred in p-ITP (15.5% vs 10.6%). Similar to p-ITP, the use of third line therapies was infrequent in IO-ITP. No patients with IO-ITP underwent splenectomy, which was also rarely used in p-ITP. Conclusions: Our study describes treatment patterns in IO-ITP, an uncommon but challenging disease. We found that individuals with IO-ITP are generally younger and predominantly male as compared to p-ITP, highlighting different patient profiles. We further demonstrated some distinctions in the management of these two conditions, possibly suggesting variable response to therapy. Prospective studies are needed to better understand the determinants of such therapeutic choices and outcomes.

AHOD2131: A Randomized Phase 3 Response-Adapted Trial Comparing Standard Therapy with Immuno-Oncology Therapy for Children and Adults with Newly Diagnosed Stage I and II Classic Hodgkin Lymphoma

Background: Chemotherapy in combination with radiotherapy (RT) is the standard for early-stage (ES) Hodgkin lymphoma (cHL). Despite high cure rates (12-year overall survival (OS) >93%), there is room to improve short and long-term outcomes for children and adults with ES cHL. Incorporation of immunotherapy (IO) into front line treatment of ES cHL is an opportunity to both improve progression-free survival (PFS) and maintain OS, while minimizing long-term morbidity and mortality by reducing exposure to RT and high-dose chemotherapy. Study Design and Methods: HL leaders of the NCTN groups, expert HL researchers and physicians, and representatives from the Cancer Therapy Evaluation Program (CTEP) formed a working group in April 2020 with the goals of harmonizing treatment approaches for ES cHL across pediatric and adult patients and reaching consensus regarding the optimal study design for incorporating IO therapy into frontline treatment. Study champions identified from each of the North American cooperative groups [Children's Oncology Group (COG), SWOG, ECOG-ACRIN, Alliance, NRG] and experts in imaging, radiation oncology, lymphoma biology and patient-reported outcomes (PROs) were included. The resulting COG-led clinical trial, AHOD2131, represents the largest ES cHL trial in the history of North American cooperative groups and the first to enroll patients across the age continuum. AHOD2131 (NCT05675410; Figure) is a randomized, phase 3 trial enrolling patients ages 5 to 60 years with newly diagnosed, previously untreated stage I and II cHL and will investigate the addition of the CD30-antibody drug conjugate brentuximab vedotin (Bv) with PD-1 blockade (nivolumab) compared to standard chemotherapy +/- RT. Since the April 2023 activation, 97 North American sites have activated the trial, and 21 participants have enrolled. Target enrollment is 1875 patients over 5 years of accrual, for an estimated 1782 eligible and evaluable patients. The primary objective is to compare the 3-year PFS of patients with ES cHL treated through a response-adapted, superiority design with either standard therapy or with an IO approach (BV + nivolumab). All patients will be stratified as favorable or unfavorable based on disease risk features at enrollment. Based on initial response assessment by PET/CT (via central review) after 2 cycles of ABVD, patients were classified to PET2 positive (SER, defined as 5 Point Score 4 or 5, ~15% of patients) and PET negative (RER). Those who are PET positive will receive involved site RT (ISRT). The SER and RER patients will be randomized to standard chemotherapy vs. IO therapy respectively. In addition to the primary outcome of PFS, there are 11 secondary and 10 exploratory aims. The secondary aims focus on OS, PFS of subgroups, and event-free survival at 12 years, physician-reported treatment-related adverse event (AE) rates, patient-reported AE using pediatric and adult versions of Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and the capture of representation by self-report and the use of electronic PRO data collections. The exploratory aims include the assessment of imaging central review as compared to local institutional review and the use of convolutional neural networks through artificial-intelligence machine learning. The study will examine the effect of therapy on acute and long-term adverse effects including health-related quality of life (HRQoL) and OS for up to 12 years. The study will compare patient self-report and provider AE reports and evaluate the associations of self-reported race/ethnicity and social determinants of health (SDOH)and post-progression/post-relapse OS. AHOD2131 strengthens the effort between the North American cooperative groups to conduct collaborative clinical trials and aims to harmonize an improved standard of care for ES cHL across the age continuum.

Comorbidities and Their Impact on Treatment Tolerance and Outcome in Elderly NSCLC Patients Treated with Concurrent Chemoradiation Using Proton or Photon Followed by Immunotherapy

To investigate comorbidities and their impact on treatment tolerance and survival for elderly NSCLC patients treated with concurrent chemoradiation using proton beam therapy (PBT) or intensity modulated radiation therapy (IMRT) followed by immunotherapy (IO). This is a retrospective study in senior patients (≥ 65 years) with inoperable locally advanced- NSCLC (LA-NSCLC) who received concurrent chemoradiation (CRT) therapy followed by adjuvant IO. Comorbidities are listed in table 1 and scored according to hazard ratios (HRs) of death. Treatment tolerance and comorbidities were compared between modalities using Fisher's exact test. Association between comorbidities and treatment tolerance was analyzed using logistic regression; association between comorbidities and survival was analyzed by Cox proportional hazards regression. Total 218 patients were included with median age of 72 (range 65-86) years. Fifty-three (24.3%) were PBT and 165 (75.7%) were IMRT. Majority patients were white ethnics, had stage III adenocarcinoma disease and good performance score, and received RT dose 60-66 Gy. The median follow-up time for the whole group was 23 months. A 97% of patients had ≥1, and 62% had ≥4 comorbidities. The combined comorbidity scores ranged from 0 to 25. No significant difference in comorbidities between modalities except IMRT had more patients with COPD (36% vs. 51%, p = 0.047). Rates of hospitalization and ER visit during CRT+IO were 28% and 5%, respectively. Rates of IO discontinuation and interruption were 55% and 8%, respectively. Patients received >6 months IO had significantly lower risk of death (HR: 0.25, p<0.001). No significant difference in treatment tolerance between modalities. In multivariable analysis, atrial fibrillation, pulmonary disease, and depression were the comorbidities associated with hospitalization during CRT+IO (p<0.05); dementia was the comorbidity associated with IO interruption (p = 0.042); heart failure, COPD, asthma, osteoporosis and HIV were the comorbidities associated with poor OS (p<0.05). Combined comorbidity score was associated with OS with HR of 1.13 (p<0.001) with adjustment of race, GTV and induction chemotherapy. Comorbidities were associated with hospitalization and IO interruption during the whole course of CRT and IO therapy, with increased IO discontinuation which negatively impacted survival. Evaluating and scoring comorbidities at diagnosis could be a useful method to predict risk of death before treatment start.

The association between systemic anticancer therapy (SACT) at the end of life (EOL) and acute care use among patients treated at oncology practices participating in the Oncology Care Model (OCM).

6580 Background: Receipt of chemotherapy near EOL has been shown to harm patient and caregiver experience, increase hospitalizations, intensive care unit (ICU) and emergency department (ED) use and drive-up costs. As rates of chemotherapy at EOL have declined, we have seen increases in the rates of immunotherapy at EOL. It is unknown whether use of EOL immunotherapy is associated with the same pattern of higher downstream acute care use and cost. Using data from OCM, a Centers for Medicare and Medicaid Services (CMS) alternative payment model, we evaluated the relationship between SACT type and acute care utilization within 30 days of death. Methods: Using anonymized Integra Connect data for OCM episode claims attributed to 8 multi-site OCM practices between July 2016 and December 2021, we stratified patients by SACT type received within 30 days of death (immunotherapy (IO), chemotherapy (CT), or none) and used chi-square tests to compare the proportion of decedents who had inpatient admission, ICU stay, ED visits without inpatient admission, and hospice use within 30 days of death. Results: Among 14,169 OCM decedents, 2,227 (15.7%) received IO within 30 days of death, 6,627 (46.8%) received CT and 5,315 (37.5%) received no SACT (table). Patients who received no SACT at EOL were significantly more likely to start hospice within 30 days of death (76%) and to be in hospice for ≥3 days prior to death (61%) compared with IO (65% and 40%) and CT patients (59% and 37%) respectively (all p-values&lt;0.05). Patients who received IO or CT were significantly more likely to have an inpatient stay within 30 days of death (66% and 68% respectively) compared with patients who received no SACT at EOL (58%, p-values &lt;0.001). No difference in ED visits within 30 days of death between IO (18%), CT (20%), and no SACT (19%) p &lt; 0.270. Conclusions: Patients who received chemotherapy or IO therapy within 30 days of death had higher proportion of inpatient admissions, ICU stay and lower rates of hospice than patients who received no SACT at the EOL. Patients who did not have any SACT at EOL were more likely to utilize hospice services and for a longer time. Further research should explore whether these findings are generalizable to patients outside of OCM and the magnitude of costs associated with these acute care metrics. [Table: see text]

Real-world assessment of treatment effectiveness in patients with advanced non-small cell lung cancer (aNSCLC) with MET exon 14 skipping (METex14).

e21112 Background: Capmatinib is approved for patients (pts) with advanced stage (a)NSCLC harboring METex14. However, there is limited data on capmatinib activity in comparison to other approved therapies. We assessed real-world (rw) clinical outcomes of pts with aNSCLC with METex14 who initiated treatment with capmatinib, immunotherapy (IO), or chemotherapy (CT) regimens. Methods: In a retrospective chart review, data were abstracted by a sample of oncologists invited nation-wide in the US who randomly selected prespecified numbers of charts, with larger sampling targets for capmatinib and IO therapies. Eligible pts were aged ≥18 years, had stage ≥IIIB NSCLC and METex14; received first-line (1L) systemic therapy after 1 January 2017 with follow up of ≥6 months after starting 1L therapy (except death) as of the data abstraction date; and did not receive MET inhibitors other than capmatinib. Clinical outcomes included best overall real world response rate (rwORR), progression-free survival (rwPFS), overall survival (OS), and time to treatment discontinuation (TTD). RwORR was assessed using rw-RECIST guided by RECIST 1.1 criteria or physician documentation. All measures were descriptively analyzed. Time-to-event outcomes were assessed per line of therapy via Kaplan-Meier methods. Results: In total, 287 eligible pts were identified. Median age was 63.3 years, 71% were male, 41% were non-White, and 49.5% were treated in community settings. 15 pts had brain metastasis at diagnosis. Pts who received 1L capmatinib had higher rwORR and longer rwPFS, OS, and TTD than pts who received 1L IO mono or CT alone or in combination (Table 1). Pts treated with second-line (2L) capmatinib had higher rwORR than other treatments but was a smaller pt population. Conclusions: Our analysis suggests that capmatinib in aNSCLC with METex14 yields numerically better clinical outcomes than IO or CT alone or in combination. These findings support use of capmatinib in this setting and may inform clinical decision making in routine practice. [Table: see text]

Real world prognostic utility of body mass index and platelet lymphocyte ratio in first-line immunotherapy response in stage IV non-small cell lung cancer.

e21092 Background: Meta-analyses show that increasing body mass index (BMI) may be associated with improved overall survival (OS) and progression free survival (PFS) compared to those with lower BMIs in patients receiving immunotherapy (IO). Pretreatment elevated platelet lymphocyte ratio (PLR) has been attributed to inferior PFS and OS in patients receiving IO. Our study evaluated real world data of Stage IV Non-Small Cell Lung Cancer (NSCLC) patients receiving first line (1L) treatment regimens involving immunotherapy while evaluating prognostic utility of BMI and PLR. Methods: Of the patients treated at USC Norris Comprehensive Cancer Center and LAC+USC Medical Center from 2015-2022, we looked at 75 Stage IV patients without EGFR, ALK, ROS1 mutations who received 1L IO therapy. Primary outcomes included PFS and OS from time of IO with a particular interest for patients with pre-treatment BMI &lt; 22 and PLR &gt; 180. Patients with previous IO exposure were excluded. Kaplan-Meier analysis using log-rank test was performed to evaluate for OS. Multivariate Cox proportion hazards regression was used for multivariate analysis of OS. Results: The median age at start of IO was 67.5 years with 49 (65.3%) males. 24 (32.0%) had BMI &lt; 22. 40/70 (57.7%) had PLR &gt; 180 at the start of 1L IO. Adenocarcinoma was the most common histology 50 (66.7%). 22 (29.3%) had PD-L1 &gt; TPS 50% and 20 (26.7%) had PD-L1 TPS 1-49%. Pembrolizumab was the most common IO used 60/75 (80%) and 43/75 (57.3%) received chemotherapy with IO. Patients with a BMI &lt; 22 had an inferior OS (BMI &lt; 22: 13.1 vs. BMI &gt; 28: 37.4 months (mos), p-value = 0.0420) with a trend towards worse PFS (BMI &lt; 22: 6.2 mos vs. BMI &gt; 28: 16 mos, p = 0.1702). Patients with PLR &gt; 180 had an inferior PFS (4.4 vs. 11.1 mos, p-value = 0.025) and OS (8.3 vs. 23.0 mos, p-value = 0.0277). A composite of BMI &lt; 22 and PLR &gt; 180 had the worst OS (p-value = 0.0385) with a trend towards worse PFS (p-value = 0.1702). (Table 1) Multivariate analysis for OS controlling for age, smoking, gender, PD-L1 TPS, and histology showed that BMI (HR: 0.8739, 95% CI: 0.7966-0.9492) and PLR &gt; 180 (HR: 2.286, 95% CI: 1.102-4.916) were significant for higher mortality risk. Conclusions: Patients with a composite profile of BMI &lt; 22 and PLR &gt; 180 had a significantly worse OS. This highlights the importance for pre-treatment screening for low BMI and high PLR to help provide additional supportive care in these patients prior to IO therapy. [Table: see text]

Abstract 5706: ImmunoPROFILE: A prospective implementation of clinically validated, quantitative immune cell profiling test identifies tumor-infiltrating CD8+ and PD-1+ cell densities as prognostic biomarkers across a 2,023 patient pan-cancer cohort treated with different therapies

Abstract Tumor-infiltrating lymphocyte (TIL) density has been identified as a prognostic and predictive biomarker in select tumors treated with defined therapies. These observations suggest that TILs may be general markers of patient outcomes, but evidence in support of this hypothesis has been limited by small cohorts. We validated ImmunoPROFILE, a multiplexed immunofluorescence (MIF)-based assay coupled with machine-learning-based image analysis, to identify and quantify tumor cells (cytokeratin, PAX5, PAX8, SOX10), T cells (CD8), T-regulatory cells (FOXP3), exhausted cells (PD-1) and immunosuppressive tumor and immune cells (PD-L1). We applied the MIF panel to specimens from patients collected prospectively over three years and analyzed 2,023 cases across 27 tumor types. The association between biomarkers and overall survival (OS) was investigated using Cox models controlling for patient risk factors such as cancer type, metastatic vs. primary disease, age, and gender. Multivariable biomarker selection was based on likelihood ratios. The assay was highly robust (success rate 97%), reproducible (inter-scanning and intra-staining density controls within 1 SD, inter-staining PD-L1 scores ≤11% CV), and operator-independent (R2 &amp;gt;0.7 to &amp;gt;0.9 for each biomarker and 95% concordance in PD-L1 score-based interpretation between technicians). From whole slide images, a total of 11,932 individual regions of interest were analyzed across the cohort, resulting in &amp;gt;50 million spatially-resolved single cells which were summarized into cell population densities and PD-L1 scores. High densities of CD8+ (&amp;gt;64/mm2, p&amp;lt;0.0001), PD-1+ (&amp;gt;50/mm2, p&amp;lt;0.0001), and FOXP3+ (&amp;gt;30/mm2, p&amp;lt;0.0001) T cells were associated with longer overall survival (OS) irrespective of therapy and across all cancer types. PD-L1 metrics were not associated with OS (p=0.43). Compared to patients with low densities of CD8+ and PD-1+ cells, high densities of at least one of these cell types had better OS (Both high, HR: 0.49, 95% CI: 0.41 - 0.59; CD8+ high, HR: 0.63, (0.48 - 0.82); PD-1+ high, HR: 0.71, (0.54 - 0.93)). The results were consistent in the subset of patients (N=1572) who did not receive immunotherapy (IO). In patients who received IO therapy (N=451), only PD-1+ T-cell density associated with OS (HR: 0.48, (0.36 - 0.65)). To our knowledge, this is the first enterprise-level immune biomarker assay using multiplexed staining, digital imaging, and machine learning to be applied in a prospective manner to clinical specimens at scale. We found that select immune cell densities are prognostic across cancer types and therapies and demonstrated that quantification of multiple cell populations yields better prognostic power than single marker analyses. Citation Format: James Lindsay, Bijaya Sharma, Kristen D. Felt, Anita Giobbie-Hurder, Ian Dryg, Jason L. Weirather, Jennifer Altreuter, Tali Mazor, Priti Kumari, Joao V. Alessi, Ajit J. Nirmal, Michael P. Manos, Ananth R. Kumar, William Lotter, Ethan Cerami, Burce E. Johnson, Neil I. Lindeman, Lynette M. Sholl, Jonathan A. Nowak, Scott J. Rodig. ImmunoPROFILE: A prospective implementation of clinically validated, quantitative immune cell profiling test identifies tumor-infiltrating CD8+ and PD-1+ cell densities as prognostic biomarkers across a 2,023 patient pan-cancer cohort treated with different therapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5706.

Financial toxicity from first-line TKI plus IO therapies for advanced renal cell carcinoma.

634 Background: Since the approval of sunitinib for the treatment of advanced renal cell carcinoma (RCC), the first-line treatment landscape has drastically altered with combination tyrosine kinase inhibitor (TKI) plus immunotherapy (IO) regimens. Despite improvements in survival, it remains unclear if these therapies are cost prohibitive for patients or hospitals compared to prior standard of care sunitinib. Methods: Approved TKI plus IO therapies were identified using the US FDA Oncology Announcements website and confirmed with NCCN Guidelines (Version 3.2023). Cost per unit was identified using public data (Lexicomp or manufacturer’s website). We calculated total cost of each treatment regimen using the cost per unit for each therapy and the median duration on treatment as reported in each combination therapy's clinical trial publication. Results: Average PFS benefit from combination TKI plus IO therapies was 8.1 months (range 4-14.7) in comparison with sunitinib. Average cost of TKI plus IO therapy was $443,839.32 compared with $199,541.44 for sunitinib therapy. Conclusions: Average increase in cost of TKI plus IO therapy compared to sunitinib was $244,297.88. For every month of PFS benefit with TKI plus IO combination therapy, there was on average $30,160.23 cost added per month. These increased costs may be prohibitive for many patients and hospitals, particularly in low- and middle-income countries (LMICs). [Table: see text]

Characterization of clinical outcomes among patients with advanced chromophobe renal cell carcinoma (ChRCC) treated with first-line immunotherapy (IO)-based regimens.

654 Background: IO-based regimens have demonstrated substantial efficacy in the management of metastatic clear-cell RCC (mccRCC), where they currently represent the standard of care. ChRCC has a dismal prognosis in the metastatic setting. Recent clinical trials evaluating IO-based regimens across non-ccRCC subtypes identified a preliminary poor response in advanced ChRCC, but were limited by low sample sizes. We sought to comprehensively evaluate the outcomes of patients with ChRCC treated with IO-based regimens. Methods: Using real-world data from the International Metastatic RCC Database Consortium (IMDC), we conducted a retrospective analysis of patients with advanced ChRCC who received IO-based therapies, including dual IO therapy or IO + VEGF targeted therapy (VEGF-TT), in the first-line setting. The primary outcome was overall survival (OS). Secondary outcomes included time to treatment failure (TTF) and ORR. Cox proportional hazards models were used to adjust for age and IMDC risk groups as covariates. A logistic regression was used to determine the association between the odds of achieving a response and RCC subtype. Results: We identified 31 patients with advanced ChRCC and 856 patients with ccRCC treated with IO-based therapies in the first-line setting, with a median age of 61.5 years (IQR: 51.5-69.0). Compared to patients with ccRCC who received IO-based therapies as initial regimens, patients with ChRCC had a lower OS (median OS: 24.7 vs. 50.5 months, respectively; p&lt;0.001) and a lower TTF (median TTF: 4.5 vs. 11.0 months, respectively; p&lt;0.001). Among patients with an evaluable objective response, the ORR was lower among patients with advanced ChRCC, as opposed to those with ccRCC (ORR: 12.0 vs 47.1%, respectively; p&lt;0.001). When evaluating first-line treatment with VEGF-TT monotherapy (sunitinib or pazopanib), no difference in outcomes was found between patients with ChRCC (n=122) and ccRCC (n=6,379) in relation to the primary endpoint of OS, while TTF and ORR suggested better outcomes for ccRCC (Table). Conclusions: In this real-world study, patients with metastatic ChRCC appear to display poor clinical outcomes even with IO-based regimens, as compared to ccRCC. The molecular determinants of poor response require further investigations. [Table: see text]

Real world prognostic utility of platelet lymphocyte ratio and nutritional status in first-line immunotherapy response in stage IV non-small cell lung cancer

BackgroundElevated platelet lymphocyte ratio (PLR) and low body mass index (BMI) are associated with inferior survival in non-small cell lung cancer (NSCLC) patients receiving immunotherapy (IO). We evaluated real-world prognostic utility of PLR, BMI, and albumin level in stage IV NSCLC patients receiving first line (1L) IO. MethodsWe identified 75 stage IV patients who received 1L IO therapy at USC Norris Comprehensive Cancer Center and Los Angeles General Medical Center from 2015 to 2022. The primary outcome was overall survival (OS) from time of IO with attention to pre-treatment BMI < 22, albumin < 3.5 g/dL, and PLR > 180. ResultsMedian age was 66.5 years with 49 (65.3%) males. 25 (33.3%) had BMI < 22. 45/75 (60%) had PLR > 180. Patients with BMI < 22 had inferior OS (13.1 months (m) vs. 37.4 m in BMI > 28, p-value = 0.042) along with patients with albumin<3.5 g/dL (OS: 2.8 m vs. 14.6 m, p-value = 0.0027), and patients with PLR>180 (OS: 8.7 m vs. 23.0 m, p = 0.028). Composite BMI < 22, PLR > 180 had the worst OS, p-value = 0.0331. Multivariate analysis controlling for age, smoking, gender, PD-L1 tumor proportion score (TPS), and histology (adenocarcinoma, squamous, adenosquamous, and large cell) showed that BMI (HR: 0.8726, 95% CI: 0.7892–0.954) and PLR > 180 (HR: 2.48, 95% CI: 1.076–6.055) were significant in OS mortality risk. ConclusionPatients with a composite of BMI < 22, albumin < 3.5 g/dL, and PLR > 180 had significantly worse OS. This highlights the importance of screening for poor nutritional status and high PLR to better inform stage IV NSCLC patients receiving IO therapy of their prognosis and supportive care. MicroAbstractWe evaluated real-world prognostic utility of platelet lymphocyte ratio (PLR), body mass index (BMI), and albumin level in 75 Stage IV NSCLC patients receiving first line IO. Patients with a composite of BMI < 22, albumin < 3.5 g/dL, and PLR > 180 had significantly worse OS. This highlights the importance of screening for poor nutritional status and high PLR to better inform stage IV NSCLC patients of their prognosis and to emphasize supportive care needs.

New Immuno-oncology Targets and Resistance Mechanisms.

Immune checkpoint inhibition (ICI) has revolutionized the field of non-small cell lung cancer (NSCLC); currently, most patients with advanced disease receive upfront ICI either alone or in combination with chemotherapy. These advances have recently extended into early-stage NSCLC, with ICI incorporation into neoadjuvant and adjuvant treatment regimens. However, despite these successes, immunotherapy (IO) resistance remains a fundamental challenge in NSCLC, introducing a central quandary of how to precisely select the appropriate IO therapy or IO combination therapy for each individual patient. To address this vital need in the field, there has been an explosion of research in immuno-oncology to identify mechanisms of resistance, ranging from genomic alterations in the tumor to immunosuppressive conditions in the tumor microenvironment (TME). There remain many questions about how this complex interplay between the tumor and the immune microenvironment translates into clinical phenotypes of primary and acquired resistance. In NSCLC, a number of novel therapeutics are being developed to prevent and overcome resistance to ICI. Particular promise has been shown with therapeutics targeting novel T cell immune checkpoint inhibitors and targeting innate immune cells in the TME, chief among these cells are natural killer cells, neutrophils, and macrophages. Further research into tissue-based and non-invasive biomarkers that can be prospectively integrated into therapeutic trial design will be critical to advance the field's understanding of individual resistance patterns and enable the ultimate goal of precision immuno-oncology.

Clinical Outcomes of Patients with Recurrent Microsatellite-Stable Endometrial Cancer in Early-Phase Immunotherapy Clinical Trials.

Simple SummaryThere is a crucial need to improve treatment regimens in patients with recurrent endometrial cancer. Although immunotherapy treatments have shown impressive benefit in microsatellite instability-high endometrial cancer, they have been less predictable in the majority of endometrial cancers, which are microsatellite stable. Our aim was to characterize clinical outcomes in patients with recurrent microsatellite stable endometrial cancer treated in early-phase immunotherapy clinical trials in order unravel treatment regimens that would improve response and survival. Our findings suggest that utilizing immunotherapy in combination with other non-immunotherapy agents resulted in greater duration of disease control and improved survival outcomes compared to immunotherapy only (monotherapy) or in combination with other immunotherapy agents. Future studies are needed to validate these findings.Recurrent microsatellite stable (MSS) endometrial cancer has poor response to conventional therapy and limited efficacy with immune checkpoint monotherapy. We conducted a retrospective study of recurrent MSS endometrial cancer patients enrolled in immunotherapy-based clinical trials at MD Anderson Cancer Center between 1 January 2010 and 31 December 2019. Patients were evaluated for radiologic response using RECIST 1.1 criteria, progression-free survival (PFS), and overall survival (OS). Thirty-five patients were treated with immune checkpoint inhibitors: 8 with monotherapy, 17 with immunotherapy (IO) in combination with another IO-only, and 10 with IO in combination with non-IO therapy. Among those treated with combination IO plus non-IO therapy, one had a partial response but 50% had clinical benefit. Patients who received combination IO plus non-IO therapy had improved PFS compared to those who received monotherapy (HR 0.56, 95% CI 0.33–0.97; p = 0.037) or combination IO-only therapy (HR 0.36, 95% CI 0.15–0.90; p = 0.028) and had improved OS when compared to monotherapy after adjusting for prior lines of therapy (HR 0.50, 95% CI 0.27–0.95; p = 0.036). The potential beneficial clinical outcomes of combination IO plus non-IO therapy in MSS endometrial cancer should be validated in a larger study.

Abstract 6176: CD56 dim+ immune infiltration and reprogrammed TMEs associated with response to neoadjuvant anti-PD-1 immunotherapy plus concurrent chemoradiotherapy in locally advanced gastric or gastroesophageal junction adenocarcinoma

Abstract PURPOSE Neoadjuvant immunotherapy (IO) combined with concurrent chemoradiotherapy (cCRT) showed a good efficacy in treatment of locally advanced gastric or gastroesophageal junction adenocarcinoma (G/GEJC) patients. However, the mechanism of therapeutic efficacy on tumor cells and the tumor microenvironment are still unknown. We aimed to characterize the microenvironment of immune cell infiltration at baseline and post-treatment of the patients in SHARED trial (ChiCTR1900024428). METHODS We prospectively enrolled 18 advanced G/GEJC patients who received IO (sintilimab, anti-PD-L1) in combination with cCRT therapy and resection in Nanjing Drum Tower Hospital. The pre-treatment tumor biopsies samples and post-treatment surgical specimens of all patients were measured for dynamic tumor microenvironment (TME) using mIHC (immune cell markers: CD3, CD4, CD8, FoxP3, CD20, CD56, CD68, CD163, PD-1, PD-L1) in a CLIA-certified laboratory. Twenty-five samples were successfully examined,including 10 paired pre-treatment biopsies and post-treatment specimens, three sole pre-treatment biopsies and two sole post-treatment specimens. RESULTS Among 18 patients who completed neoadjuvant treatment and resection, eight (44.4%) achieved pathological complete response (pCR), and 10 (55.6%) achieved non-pCR (six MPR and four non-MPR). Evaluable pre-treatment samples revealed a significantly higher CD56 dim+ immune infiltration (P=0.018) in pCR tumors compared with non-pCR tumors. Three patients harbored tertiary lymphoid structures (TLSs) in pre-treatment biopsies, two out of three achieved pCR and one achieved MPR. Another one patient harbored TLSs in post-treatment specimens and achieved pCR. No difference was found in all evaluable post-treatment specimens, when compared with paired pretreatment biopsies. Strikingly, significant post-treatment increases in CD3+ immune infiltration (P=0.0366) and CD4+FoxP3+ immune infiltration (P=0.0277) were observed in pCR tumors, with no significant difference in non-pCR tumors. CONCLUSIONS The different response to IO plus cCRT therapy in locally advanced G/GEJC patients and be explained by the difference in TME including the baseline CD56 dim+ immune infiltration, TLSs status and the reprogrammed immune infiltration induced by IO PLUS cCRT therapy. Further large population based studies are warranted to validate the response mechanism. Citation Format: Jia Wei, Qin Liu, Hui Chen, Xin Zhang, Feilong Zhao, Yao Fu, Ju Yang, Yue Wang, Shiqing Chen, Xiaochen Zhao, Yuezong Bai, Wenxian Guan, Baorui Liu. CD56 dim+ immune infiltration and reprogrammed TMEs associated with response to neoadjuvant anti-PD-1 immunotherapy plus concurrent chemoradiotherapy in locally advanced gastric or gastroesophageal junction adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6176.

Progression and mortality post-immunotherapy discontinuation among patients with BRAFV600-mutant (BRAF+) metastatic melanoma.

9531 Background: Immunotherapy (IO) is commonly used to treat BRAF+ metastatic melanoma (MM) patients in the first line (1L) setting and has demonstrated durable outcomes in clinical trials. However, most patients discontinue IO therapy for toxicity, disease progression, or other reasons. To date, no multi-center or nationwide US-based study has examined treatment patterns and outcomes for patients with BRAF+ MM post discontinuation of 1L IO. The aim of this study is to describe real-world treatment patterns and outcomes among patients who discontinued 1L IO. Methods: This retrospective cohort study used the Novartis BRAF+ meLanoma patients ObsErvational (NOBLE) database, the harmonized customized data from Flatiron and ConcertAI. Patients were ≥18 years old, had a diagnosis of BRAF+ MM, were treated with pembrolizumab, nivolumab, or ipilimumab + nivolumab on or after 9/1/2014, and then discontinued 1L therapy. Reason for discontinuation was extracted from medical records. Descriptive statistics were used to describe baseline characteristics and treatment patterns. Kaplan–Meier curves were used to analyze time to progression or death (TTPD) and time to death (TTD). Results: Of the 898 included patients (mean age: 61 years; male: 65%); 46% initiated ipilimumab + nivolumab, 24% nivolumab, and 30% pembrolizumab. The most common reasons for 1L discontinuation were toxicity (26%) and progression (25%). Medical records noted 5.3% completed therapy on discontinuation and 34.5% provided no reason of discontinuation with median duration of therapy (MDOT) of 379 and 138 days respectively. At 6 months, 34 % (n = 303) remain on IL IO. MDOT for patients who discontinued IO due to toxicity and those who discontinued due to progression were 54 and 63.5 days respectively. Patients who discontinued due to toxicity had a median time of 142 days to next treatment. TTPD was best for patients who discontinued therapy due to completion or toxicity (6-month progression rate: 13% and 20%). Patients who discontinued due to progression did especially poorly (6-month progression rate: 59%). About 33% of patients (n = 296) needed second line (2L) therapy, and the majority (80.7%) received combination BRAF+ targeted therapy. Overall, 38% and 50% of patients died post IO discontinuation for any reason at 1 and 2 years, respectively. 31% of patients had brain metastases and a greater proportion (56%) died within a 2-year period compared with those without brain metastases (56% vs 49%, p = 0.0036). Conclusions: IO, although effective, is not curative for all patients. A significant number of patients discontinue therapy due to progression. Patients with BRAF+ MM who progress early on 1L IO therapy have a high risk of death and should be considered for other therapy options, including targeted therapy.

Bevacizumab for radiation necrosis of the brain or steroid-refractory edema in patients with melanoma receiving immune checkpoint inhibitors.

e14008 Background: For patients with melanoma brain metastasis (MBM) treated with stereotactic radiosurgery (SRS), 5-6.5% develop radiation necrosis of the brain (RNB), which is commonly treated with corticosteroids (CS). Nonetheless, high-dose CS may reduce efficacy of immunotherapy (IO). Bevacizumab (BV) has been shown to reduce symptoms and peritumoral edema associated with RNB. However, data on the efficacy and toxicity of BV in patients with MBM who also receive IO is limited. We aimed to describe clinical features and outcomes of patients with MBM who received BV and were also treated with IO. Methods: Under an IRB-approved protocol, patients with MBM who developed RNB or steroid-refractory edema (SRE) and were treated with BV were identified. The selection criteria were as follows: (1) one or more MBM; (2) prior SRS for MBM; (3) development of RNB or SRE detected radiographically or based on expert opinion; (4) treatment with one or more cycles of BV; (5) treatment with IO for metastatic melanoma. Results: In this single-center retrospective series, 8 patients received IO and BV: 4 concurrently and 4 patients received IO immediately prior to or after BV. IO therapy included ipilimumab-nivolumab, nivolumab alone or pembrolizumab. Median number of MBM was 3.6 (range, 1-8) and median number of RNB/SRE foci were 1.125 (range, 1-2). Median time from diagnosis of RNB/SRE to initiation of BV was 1.4 months (range, 0.5-3 months). BV dosing regimen was 5 mg/kg every 2 weeks, 7.5 mg/kg every 3 weeks or 10 mg/kg every 2 weeks. 71% (5 of 7) patients who required CS for RNB/peritumoral edema symptoms at the time of starting BV were able to taper CS after receiving BV or stop CS completely. This allowed for 4 of these patients to subsequently start or resume IO. 28% (2 of 7) patients had increasing neurological symptoms during CS taper and required an increase in CS dosing. Only 1 patient was not on CS at the time of BV initiation. 75% (6 of 8) cases attained intracranial radiologic response, with documented decreased edema or tumor size, or resolution of enhancement on MRI; 1 patient had stable disease after BV; and 1 patient had continued clinical deterioration despite BV. 62.5% (5 of 8) patients had no adverse events from BV, but 37.5% (3 of 8) had DVT/PE, 1 requiring a thrombectomy, and 1 additionally had perforated diverticulitis. Median follow-up time from BV administration was 17.94 months (range, 1-58 months), with 75% (6 of 8) patients with survival &gt; 10 months. Conclusions: Treatment of RNB/SRE with BV in patients with MBM receiving IO appears to be effective and relatively well tolerated, though with occasional serious adverse events. BV led to improvement of symptoms and allowed for CS taper in a substantial proportion of patients. By reducing CS requirement, BV may permit continuation of IO, which leads to durable survival in a large proportion of patients.