Effect of Prior Antibiotic or Chemotherapy Treatment on Immunotherapy Response in Non-small Cell Lung Cancer

Background Treatment outcomes of advanced non-small cell lung cancer (NSCLC) have substantially improved with immune checkpoint inhibitors (ICI), although only approximately 19% of patients respond to immunotherapy alone, increasing to 58% with the addition of chemotherapy. The gut microbiome has been recognized as a modulator of ICI response via its priming effect on the host immune response. Antibiotics as well as chemotherapy reduce gut microbial diversity, hence altering composition and function of the gut microbiome. Since the gut microbiome may modify ICI efficacy, we conducted a retrospective study evaluating the effects of prior antibiotic or chemotherapy use on NSCLC patient response to ICI.Methods We retrospectively evaluated 256 NSCLC patients treated between 2011-2017 at Moffitt Cancer Center with ICI ± chemotherapy, examining the associations between prior antibiotic or chemotherapy use, overall response rate and survival. Relative risk regression using a log-link with combinatorial expectation maximization algorithm was performed to analyze differences in response between patients treated with antibiotics or chemotherapy versus patients who didn’t receive antibiotics or chemotherapy. Cox proportional hazards models were constructed to evaluate associations between risk factors and overall survival. Results Only 46 (18% of 256) patients used antibiotics prior to and/or during ICI treatment, and 146 (57%) had prior chemotherapy. Antibiotic users were 8% more likely to have worse overall response rate (RR:1.08; CI:0.93-1.26; p=0.321), as well as a 35% worse overall survival (HR:1.35; CI:0.91-2.02; p=0.145), although results were not statistically significant. However, prior use of chemotherapy was significantly associated with poor ICI response (RR:1.24; CI:1.05-1.47; p=0.013) and worse overall survival (HR:1.47; CI:1.07-2.03; p=0.018). Conclusions Patients receiving antibiotics prior to and/or during ICI therapy might experience worse treatment outcomes and survival than unexposed patients, although these associations were not statistically significant and hence warrant further prospective study. Prior chemotherapy significantly reduced ICI response and overall survival. Antibiotic or chemotherapy exposure may negatively impact ICI response, perhaps through disruption of the eubiotic gut microbiome.

Comorbidity Evaluation Identifies Smoking Dose Density to be Associated with TP53 Mutation in Myeloid Malignancies

Background: Inflammation and aging are factors associated with mutagenicity. In acute Myelogenous Leukemia (AML), detectable mutations (mut) are a powerful tool for identification of patients (pt) at a higher risk for relapse. One frequently observed mutation is TP53, which is particularly unresponsive to treatment. Known risk factors for TP53 acquisition include prior chemotherapy or radiation exposure. It is possible that TP53 mut initiates at low allele frequency and expands in a "permissible marrow microenvironment". Cell extrinsic inflammation, collectively called extracellular stressor, is a theory of mutation acquisition which is gaining momentum given its recently recognized role in clonal initiation, expansion, and dominance. Smoking is one such possible extracellular stressor that dramatically increases risk of human cancer. Lung tissue directly exposed to smoking develops higher frequency of mut; however, other tissue not directly exposed (e.g. bladder, pancreas) exhibit similar mutation frequencies. This suggests that active smoking metabolites systemically induce inflammation and/or mutagenicity. Indeed, TP53 and ASXL1 mut have been associated with clonal hematopoiesis (CH). In this study, we seek to create "proof of clinical concept" for association between smoking "dose" and TP53 myeloid malignancy development when controlled by an age-adjusted effect. Methods: After IRB approval, AML and Myelodysplastic Syndrome (MDS) AML patients with available Next Generation Sequencing (NGS) were isolated from MDS/AML databases. "Smoking dose" was estimated in patients exhibiting or not exhibiting TP53 mut by standard pack-year calculation. Demographics, clinical, and laboratory categorical and continuous variables were analyzed by chi-square and t-test using SAS software. Logistic regression analysis allowed for identification of variables with independent predictive value for TP53 acquisition. Results: Our cohort represented 52 patients (pt) [AML N=47/52 (90.3%) and MDS N=5/52 (9.6%)]. 23/52 (44.2%) pt harbored TP53-mut and 29/52 pt (55.8%) were part of a genomic control group harboring ASXL1, RUNX1, FLT3, NPM1, and KRAS mut. Median age for pt with and without TP53 mut was 71 y (49-81) vs 60 y (22-88), respectively, p= 0.04 [Fig. 1B]. In TP53 mutated vs TP53 unmutated group, 14/23 (60.8%) vs 13/20 (65%) pt were male. 9/23 (39.1%) and 7/20 (35%) of pt with and without TP53 mut had available smoking history. Pack-year smoking was 53.6 [20-100] and 23.2 [10-40], in pt wit and without TP53 mut, respectively, p=0.02 [Fig. 1A]. When adjusted by age and prior chemotherapy exposure, smoking dose density was the only potential factor with relevance for TP53 acquisition (p=0.05). Conclusions: In myeloid malignancies, our data suggests that TP53 acquisition is associated with a dose dependent smoking history. This smoking dose dependency seems to be independent from aging and prior chemotherapy exposure in AML. Previous studies have demonstrated strong associations between smoking and inflammation. It is possible that higher dosages of smoking induce marrow microenvironment inflammatory changes permissible for TP53 initiation. These microenvironmental changes may be associated with mutational signatures similar to those found in other smoking-associated malignancies, including lung adenocarcinoma. Our report adds to the body of evidence for mechanistic link between magnitude of smoking exposure and marrow environmental stress to promote selective mutagenicity, though larger study is needed. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

807 Immunotherapy related adverse events: a single center experience

BackgroundAs the role of immune checkpoint inhibitors (ICIs) expands in many malignancies, including hepatocellular carcinoma (HCC), a better understanding of the predictors of immunotherapy-related adverse events (irAEs) is needed due to the complexity that ICIs add to patient care.1–5MethodsWe conducted a single-institution retrospective chart review for cancer patients of any type who received at least one ICI between January 2015 and December 2020. Demographic, social, cancer-related, laboratory, and treatment variables were collected, along with irAE data. Exploratory statistical analysis was performed to find predictors of increased irAEs.ResultsA total of 342 patients were included in the study: 133 women and 209 men. Median age was 65 years. The most common cancers were lung (110, 32.07%), kidney (51, 14.87%), and HCC (43, 12.54%). All patients received at least one dose of ICI (table 1); 11 received combination ICIs. One hundred and two (26.53%) patients developed irAEs of any grade (table 2). Nineteen patients (5.56%) had a grade 3 or 4 irAE; 20 patients required systemic steroids. No biologics were used for the management of severe irAEs. Patients who received prior chemotherapy were less likely to develop irAEs (odds ratio [OR] = 0.42, p = 0.0006). A history of hyperthyroidism or hypothyroidism was associated with more irAEs (p = 0.011). Combination ICI led to more irAEs overall (OR = 2.91, p = 0.043), as well as grade 3 or 4 events (OR = 5.32, p = 0.008). A trend toward more grade 3 or 4 events occurred in HCC patient (OR = 2.78, p = 0.06). Older patients showed a trend toward more irAEs (p = 0.08).Worse peri-treatment renal function was associated with an increased risk of irAE (OR = 1.86, p = 0.047). A higher peri-treatment hemoglobin nadir was associated with a lower risk of irAE (OR = 0.45, p = 0.07). Several other variables had ORs or confidence intervals close to 1, including number of sessions of ICI and higher baseline AST.ConclusionsPrior chemotherapy, worse renal function, and thyroid dysfunction were associated with irAEs, whereas higher hemoglobin nadir was protective against irAE. Unlike the current literature, our study included a large number of HCC patients. The higher irAE incidence in our study could be associated with this higher number of HCC patients; however, further studies are needed.ReferencesBrahmer JR, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. JCO 2018;36:1714–1768.National Comprehensive Cancer Network. Management of Immunotherapy-Related Toxicities, 2021. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf.Kartolo A, Sattar J, Sahai V, Baetz T, Lakoff JM. Predictors of immunotherapy-induced immune-related adverse events. Curr Oncol 2018;25:e403–e410.Suresh K, et al. Pneumonitis in non–small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors. Journal of Thoracic Oncology 2018;13:1930–1939.Colen RR, et al. Radiomics to predict immunotherapy-induced pneumonitis: proof of concept. Invest New Drugs 2018;36:601–607.Ethics ApprovalThe study involving retrospective review of patient records was approved under the Institutional Review Board. All records identifying the patient was be kept confidential and, to the extent permitted by the applicable laws and/or regulations, were not be made publicly available. Patient names will not be supplied to third parties. A unique study number will be assigned to each patient. Study data stored electronically will be stored in a password-protected, encrypted computers. Paper study data will be maintained by the primary investigators in the locked research offices.ConsentN/AAbstract 807 Table 1Immune checkpoint inhibitors receivedAbstract 807 Table 2irAE incidence

ALK Rearrangement–Positive Pancreatic Cancer with Brain Metastasis Has Remarkable Response to ALK Inhibitors: A Case Report

Patients with metastatic pancreatic cancer typically have poor prognosis due to the limited effectiveness of existing treatment options. ALK rearrangement–positive is rare in pancreatic cancer, but may occur in those with KRAS-wild type. We present a 34-year-old young man with ALK rearrangement–positive and KRAS-wild pancreatic cancer who had a remarkable response to crizotinib after resistance to prior chemotherapy and re-response to alectinib after brain metastases developed. This clinical observation suggests that comprehensive molecular profiling to guide targeted therapies is not only feasible, but also significantly improves survival outcomes for a subgroup of patients with pancreatic cancer.

Efficacy of an anti-EGFR after ctDNA conversion from mutated RAS status of metastatic colorectal cancer: Results of a pilot study.

e15574 Background: This pilot study aimed at the evaluation of the efficacy of anti-EGFR therapy in patients with initially RAS-mutated metastatic colorectal cancer, whose liquid biopsy found no RAS mutation after prior chemotherapy failure. Methods: Sixteen patients with RAS-mutated metastatic colorectal cancer in the solid tumor were included, after they had received 1 to 3 prior chemotherapy lines without anti-EGFR. Before inclusion, RAS genotyping was performed in circulating tumor DNA (ctDNA) from liquid biopsy, after a median duration of ̃24 months after the initial RAS status determination. No RAS mutation was detected in the circulating tumor DNA from 9 patients (56%), who then received cetuximab-FOLFIRI. The 7 patients who had persistent RAS mutation in the liquid biopsy (44%) were treated according to standard recommendations without anti-EGFR. Results: The median progression free survival was 8.2 months [95%CL, 4.5 – 11.8] in patients without detectable ctDNA RAS mutation, as compared to 3.5 months [2.1 – 4.9] in the ctDNA mutated patients (p < 0.001). The median overall survival was 22.3 months [17.3 - 27.3] in the patients with undetectable ctDNA RAS mutation, whereas it was 4.7 months [2.6 - 6.7] in those with ctDNA RAS mutation (p = 0.013). These results suggested the efficacy of cetuximab-based chemotherapy in patients with initially RAS mutated metastatic colorectal cancer, who later displayed no detectable ctDNA RAS mutation. Conclusions: The introduction of an anti-EGFR could provide an additional treatment option for patients with metastatic colorectal cancer with apparent conversion of initial RAS mutation, based on ctDNA assessment after prior failure on anti-EGFR-free chemotherapy.

The role of selective internal radiation therapy for liver metastases from pancreatic adenocarcinoma after progression on prior chemotherapy.

e16272 Background: Selective internal radiation therapy (SIRT) has established benefit for liver metastases in colorectal cancer. Very little data exists on the use of SIRT for liver dominant metastatic pancreatic cancer. A 2015 phase II trial by Gibbs et al suggested that SIRT at diagnosis may be beneficial in liver metastases in pancreatic cancer, particularly in those who have had a previous primary resection. Methods: In this single-institute retrospective audit we identified eleven patients who had liver predominant metastatic adenocarcinoma of the pancreas who received SIRT at any stage of their treatment. Data was analysed from our electronic patient databases. Results: 11 patients with adenocarcinoma of the pancreas, who had SIRT following progression on chemotherapy were identified. 3 had a primary surgical resection. All patients had received a minimum of one line of chemotherapy and had ECOG performance status of 2 or less. The median time from diagnosis to SIRT was 13 months (range 5-24 months). Patients received Yttrium-90 microspheres with a median activity of 2.1GBq with all eleven receiving concurrent infusional 5-FU 225mg/m2/day for 7 days prior and 14 days after. The median survival after SIRT therapy was 6 months (range 2-19 months). The median overall survival from diagnosis was 20 months (range 12-31 months). SIRT appeared safe and well-tolerated with no associated 30 day all-cause mortality. One patient developed radiation induced asymptomatic portal hypertension and liver cirrhosis. Conclusions: This is the first report of the use of SIRT with radiosensitising concurrent infusional 5FU for metastatic pancreatic cancer after failure of prior chemotherapy. We conclude that SIRT with concurrent infusional 5FU offers an additional treatment option for patients with liver dominant metastatic pancreatic cancer, who maintain a good PS who have progressed on prior lines of chemotherapy. This can provide a durable treatment response and requires further exploration.

Abemaciclib combined with adjuvant endocrine therapy in patients with high risk early breast cancer who received neoadjuvant chemotherapy (NAC).

517 Background: monarchE, a phase 3, open-label, randomized study evaluating abemaciclib combined with adjuvant endocrine therapy (ET) compared to ET alone in patients with HR+, HER2-, high risk early breast cancer (EBC), resulted in a statistically significant improvement in invasive disease-free survival (IDFS) (HR = 0.713; 95% CI: 0.583, 0.871). NAC is used in patients with HR+, HER2- EBC at higher risk of recurrence despite often limited response, suggesting a need for enhanced adjuvant ET. Methods: Patients with ≥4 positive notes (LNS), or 1-3 LNS and either Grade 3 disease, tumor size ≥5 cm, or central Ki-67 ≥20% were eligible. Prior chemotherapy (NAC, adjuvant, none) was one of the stratifications factors. Prior therapy and tumor characteristics prior to study entry were collected. Here, we present the results of the prespecified subgroup of patients who received NAC. Results: Out of 5,637 randomized patients, 2056 (36.5%) received NAC. For 84.8%, the chosen regimen included anthracycline + cyclophosphamide + taxane, for 4.4%, it included anthracycline + taxane. A total of 1044 (50.8%) patients who received NAC had a radiologic tumor size between 2-5 cm and 599 (29.1%) had tumors ≥5 cm at diagnosis. 6.2%, 49.4% and 36.7% of patients had tumors with histologic Grade 1, 2, 3 respectively. 55.2% of patients had LNS ≥4+ and 44.4% had 1-3+ LNS. Central Ki-67 prior to NAC was ≥20% in 64.8% of patients with available Ki-67 results (664 (32.3%) patients had missing Ki-67 results). Evaluation of clinical and pathological measures of response will be presented. A multivariate cox regression analysis of IDFS in the intent-to-treat (ITT) population, identified prior chemotherapy as prognostic, suggesting patients who received NAC were at risk of a worse outcome. Primary outcome efficacy data for patients who received NAC are shown in the table below. Abemaciclib + ET demonstrated treatment benefit in terms of IDFS vs ET alone (HR: 0.614 95% CI: 0.473, 0.797) with 2-year IDFS rates of 87.2% vs 80.6%, respectively. The addition of abemaciclib to ET resulted in an improvement in distant relapse-free survival (DRFS) (HR: 0.609, 95% CI: 0.459, 0.809), with 2-year DRFS rates of 89.5% and 82.8%, respectively. Safety profile was similar to the overall safety population. Conclusions: Patients with HR+, HER2- EBC who received NAC were noted to be at a higher risk of recurrence. In this subgroup, abemaciclib combined with ET demonstrated a clinically meaningful treatment benefit in IDFS and DRFS, which was numerically greater than in the ITT population. Safety data were consistent with abemaciclib safety profile. Clinical trial information: NCT03155997. [Table: see text]

Proton pump inhibitor use (PPI) in patients treated with immune checkpoint inhibitors (ICI) for advanced cancer: Survival and prior therapy.

2633 Background: Emerging data suggest that concomitant medications (CM) influence response to ICI. CM impact the host microbiome which may mitigate tumor-immune responsiveness. PPI use in patients treated with ICI has been associated with worse survival. Few data exist regarding the effects of PPI use in terms of prior chemotherapy or in risk for immune related adverse events (irAE) (e.g., colitis). Methods: This retrospective study of patients with advanced cancer treated with ICI between 2011 and 2019 was conducted at The Ohio State University. Patients who received ICI as either single agent or combination were included. Clinical data was abstracted from chart review, including CM, toxicity, and survival. Overall survival (OS) was evaluated to date of death or last contact. Associations between OS and proton pump inhibitor (PPI) use were studied using log-rank tests and Cox regression analyses overall and by the groups of whether prior chemotherapy was administered and timing from chemotherapy to ICI. The associations between PPI and incidence of irAE (overall and colitis) were assessed by chi-square tests. Results: We identified 1,091 patients treated with ICI, of whom 415 (38%) received PPI at time of ICI. Most common cancers were NSCLC and melanoma; most common therapy was PD1/L1 (Table). PPI use was associated with shorter OS in patients treated as first line therapy (HR = 1.46, 95% CI = [1.11, 1.91], p=0.006) and in second line and beyond (HR = 1.30, 95% CI = [1.10, 1.53], p=0.002). PPI use was associated with shorter OS in patients treated with ICI for those without prior chemotherapy (HR = 1.47, 95% CI = [1.17, 1.86], p=0.001). When evaluated by timing from chemotherapy to ICI, PPI use was associated with shorter OS only in patients where last chemotherapy was > 1 year from ICI (HR = 1.99, 95% CI [1.15, 3.45], p=0.014) but not for patients with chemotherapy within 1 year of ICI (HR = 1.01, 95% CI = [0.79, 1.29], p=0.960). The use of PPI was not associated with incidence of irAE (p=0.317) or colitis in particular (p=0.781). Conclusions: PPI use was associated with shorter survival in patients treated with ICI across a broad variety of cancers and in first line of therapy or beyond. In patients with recent chemotherapy (<1 year), PPI use was not associated with survival, which may be due to disruption of the microbiome by chemotherapy. Further study is needed to determine the impact of CM (e.g, PPI), on outcomes of patients treated with ICI.[Table: see text]