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e21131 Background: Solid organ transplant recipients have increased risk for malignancies. Lung cancer is the second most common malignancy in this population. Those patients are usually on long-term immunosuppressive medications that may affect tumorigenesis, cancer characteristics, and treatment response. Previous studies have investigated the characteristics and outcomes of post-transplant patients with lung cancer in small-sized cohorts. However, the tumor mutational profile and detailed treatment response at different stages have not been reported. Methods: We conducted a retrospective study from a cohort of 52 solid organ transplant recipients who were diagnosed with lung cancer at Mayo Clinic from 2018 to 2021. We examined tumor molecular alteration using next generation sequencing (NGS), analyzed the treatment modalities, progression-free survival (PFS), and overall survival (OS) and compared those to the general population with lung cancer using historical data in previous large trials. Results: In our study, most transplanted solid organs are kidney (N = 28, 53.8%), followed by liver (N = 12, 23.1%) and heart (N = 9, 17.3%). The adenocarcinoma (N = 28, 53.8%) represented the most common histology, followed by squamous cell carcinoma (N = 19, 36.5%). It consisted of Stage I (30.8%), stage II (15.4%), stage III (25%), and stage IV (26.9%). The most common site of metastasis is bone (64.3%). Transplant recipients with lung cancer have a significantly high frequency of somatic BRCA 1/2 mutations (30.4%), compared to the general population with advanced lung cancer (2.1%, p < 0.001). The frequencies of TP53 mutations (52.2%) and EGFR mutations (30.4%) are also increased. For stage I patients who received surgery or radiation therapy, the disease-free survival (DFS) is 16.5 months. 9 of 14 stage IV patients received chemotherapy. The median number of cycles received is 4. The median PFS is 4.9 months, and the median OS of all stage IV patients is 6.1 months. 4 patients were found to have actionable EGFR mutations, and 3 of them were initially diagnosed with stage IIIA and received Osimertinib after progression. One stage IV patient who was post-liver transplant received pembrolizumab for up to 5 cycles before he developed aspiration pneumonia and then pursued hospice. The PFS is 3.7 months. No immune-related adverse event was reported. Conclusions: In our cohort of solid organ transplant recipients who developed lung cancer, we observed a much higher frequency of somatic BRCA 1/2 mutations, compared to the general population with lung cancer. In addition, our data suggested post-transplant patients with stage I lung cancer have a shorter disease-free survival, and patients with stage IV lung cancer have a shorter overall survival, compared to the general population with lung cancer. Further study containing a high number of solid transplant patients to validate these findings is warranted.

3584 Background: Patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed on ≥2 prior therapies have limited treatment options, with median OS ranging from 6-9 months (mo). In the dose-escalation phase of this first-in-human multicohort study (NCT02720068), the anti-lymphocyte activation gene (LAG)-3 antibody favezelimab (fave) was well tolerated alone and with pembrolizumab (pembro) across all dose levels (Lakhani, SITC, 2018, abstract O26). Here, we evaluate the safety and efficacy of fave alone or in combination with pembro in pts with advanced MSS CRC from the dose confirmation phase. Methods: Eligible pts with MSS PD-1/PD-L1-treatment-naïve mCRC that progressed on prior standard-of-care (3L+) were enrolled (cohort A) to receive the RP2D of 800 mg fave alone (Arm 1), 800 mg fave + 200 mg pembro (Arm 2C), or 800 mg fave + 200 mg pembro (MK-4280A) co-formulation (Arm 5), all Q3W. Treatment continued for 35 cycles or until progression, unacceptable toxicity, or investigator/pt decision. Pts with confirmed progression per irRECIST v1.1 on fave alone could crossover to 800 mg fave + pembro. Safety was assessed in all treated pts; efficacy in the full analysis set (FAS) of all treated pts with baseline scan. Objectives included safety (primary), ORR (RECIST v1.1 by investigator [secondary]), and DOR, PFS, and OS (exploratory). Interim analysis data cut-off was: Oct. 23, 2020. Results: A total of 20 pts received fave (Arm 1); 89 pts (including 9 crossover) received fave + pembro (Arms 2C+5); 12 pts (Arm 1) and 36 pts (Arms 2C+5), had PD-L1 CPS ≥1 tumors. At data cut-off, median follow-up was 5.8 months (mo) in Arm 1 and 6.2 mo in Arms 2C+5. Treatment-related adverse events (TRAEs) were 65% with fave (Arm 1) and 65.2% with fave + pembro (Arms 2C+5). Grade ≥3 TRAEs were 15% (Arm 1), and 20% [Arms 2C+5]). No grade 5 TRAEs were reported. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15%) with fave, and fatigue (16.9%) with fave + pembro. Confirmed ORR was 6.3% (4PR, 1CR) with fave + pembro (Arms 2C+5). No pt receiving fave alone responded. In Arms 2C+5, median DOR was 10.6 mo (range, 5.6-12.7). ORR, OS and PFS by PD-L1 status are reported in the Table. Conclusions: Favezelimab alone or in combination with pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, including with MK-4280A, compared with monotherapy most notably in pts with PD-L1 CPS ≥1 tumors. Clinical trial information: NCT02720068. [Table: see text]

9108 Background: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related death in the U.S. The median age at diagnosis is 70 years, and NSCLC is uncommon among younger individuals ( < 50 years).Overall, outcomes in NSCLC have improved significantly with targeted therapy. A prior study demonstrated patients < 50 are more likely to have targetable alterations including EGFR, ALK, ERBB2, and ROS1. Another study reported an increased prevalence of EGFR mutations in females and KRAS mutations in males with NSCLC. The comprehensive genomic landscape of NSCLC patients in different age groups and genders remains largely unknown. In our study, we aim to investigate the genomic alterations in patients with advanced NSCLC according to age and sex. Efforts that are focused on identifying targetable alterations in NSCLC will likely help personalize treatment and improve outcomes. Methods: We performed a retrospective review of de-identified data from the Guardant Health database from March 2018 through October 2020. We reviewed 34,237 profiles from patients with NSCLC who underwent molecular profiling using the plasma-based circulating-tumor DNA (ctDNA) Next-Generation Sequencing (NGS) assay Guardant360. Single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 83 genes were analyzed. We assessed for genomic differences among patients with advanced NSCLC by both sex and age (≥70 and < 70). We conducted two-tailed tests of equality of proportions comparing males to females and ≥70 to < 70. Results: Of the 34,237 profiles reviewed, somatic alterations were seen in 81.7% (n = 27,972) of the patients. The median age was 70 (range 16-102) and 55% were female. Our study demonstrated that the most common genomic alterations in both age groups and genders were TP53, EGFR, KRAS, ATM, and MET. Patients ≥70 were more likely to have ATM (21% versus 14%, p < 0.0001) and MET (12% versus 10 %, p < 0.0001) mutations than those < 70. Patients < 70 were more likely to have EGFR (30% versus 27%, p < 0.0001), STK11 (14% versus 11%, p = 0.0056), and KRAS (26% versus 24%, p < 0.0001) alterations. EGFR was seen more frequently in females (33% versus 26%, p < 0.0001). ATM (11% versus 6%, p < 0.0001) and MET (8% versus 5%, p = 0.0050) were seen more frequently in males. Conclusions: Significant differences in the distribution of targetable genomic alterations were identified among different age groups and genders in patients with advanced NSCLC. These findings highlight the importance of taking personalized approaches to diagnostic testing and treatment of advanced NSCLC.

e21069 Background: Lobectomy remains the standard of care for definitive management of stage I non-small cell lung cancer (NSCLC). Stereotactic body radiation therapy (SBRT) is considered primarily for patients who were either unwilling to have surgery or deemed to be medically unfit for surgery. Current NCCN guidelines indicate the use of CT for surveillance following curative-intent therapies and recommend CT every 6 months for 2-3 years followed by CT annually without clear guidance on how long to keep doing annual CT scans. This study aims to evaluate the patterns of lung cancer recurrence within and beyond five years post curative therapy. Methods: Patients diagnosed with stage I NSCLC and treated with either curative surgery or SBRT from 1998-2016 at Mayo Clinic Florida were identified. Through retrospective chart review, data was collected on clinical and demographic features, surveillance imaging, pathology, time to recurrence or new primary lung cancer, and location of recurrence (loco-regional vs. distant). Statistical analysis with chi-square test was performed to identify risk factors associated with recurrence. Results: In total, 203 patients with stage I NSCLC were identified with most patients treated with surgery (n = 181) compared with SBRT (n = 22). Median time of follow up is 85 months. Overall, 48 patients (23.6%) developed a recurrence, with the median time to recurrence of 22.3 (3.9-69.8) months. Most recurrences were identified within 5 years from curative therapy (42/48) with 6 patients having a recurrence between 5 and 10 years post curative therapy. Of the 37 patients followed for more than 10 years, there were no recurrences. Twenty seven patients had new primary lung cancers identified and among them, 15 were found within 5 years, 10 found between 5-10 years and 2 found beyond 10 years. Median time to new primary lung cancer was 58.1 months. A positive smoking history and stage IB were found significantly associated with lung cancer recurrence (chi-square test P = 0.007 and P = 0.04 respectively), while age, gender, histology, grade, and treatment type had no association. Conclusions: In this study of 203 patients with stage I NSCLC treated with curative intention, there was no evidence of recurrent disease after 10 years following curative therapy, questioning the utility of continued annual CT surveillance once patients hit this milestone.

9543 Background: Lung cancer is the leading cause of cancer related death in the United States in all racial groups. However, the overall death rate from lung cancer is different among white, black and Asian. Although differences in socioeconomic status and treatments received might be the contributing factors, the biology, particularly genomic alteration of cancer might also have an important impact. To date, the differences of genomic alterations among all racial patients are poorly understood. Methods: The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE, version 7.0) database was analyzed. A total of 8908 patients with lung adenocarcinoma (LUAD) were identified. Among them, 5652 patients who had comprehensive sequencing results (gene panel ≥ 275) were selected for further analysis. Patients with unknown race, undefined and Pacific Island (only 3 patients) were excluded. Finally, 5360 patients were included in the study. The prevalence and distribution of genomic alteration cross all racial groups were analyzed. Results: Overall 5951 samples from 5360 patients were collected (85.7% white, 7.9% Asian, 4.7% black, 0.2% Native American and 1.4% other). Most patients have only one sample. The median mutation counts in white, black, Asian, Native American and others are 7, 6, 5, 5, 7 respectively (Kruskal–Wallis test, P< 0.001). Asian have significantly higher rates of insertion and deletions than other races (14.8% of Asian versus 9.8% of white, 10.7% of black, 10.4% of Native American, 11.1% of other; Pearson’s chi-square test, < 0.001). TP53, EGFR, KRAS and STK11 are the most frequent alterations in white, black and other. EGFR, TP53, KRAS and APC are the most frequent alterations in Asian. STK11 mutations are rare in both Asian and Native American. Native Americans have more alterations of LRP1B, ARID2 and ATM, although the patients’ number remains small. ATM and KEAP1 mutations are also common in white and black. EGFR is the highest discrepancy gene in racial distribution. 78.9% Asian, 47.7% black, 36.4% of native American had EGFR alteration in comparison to 29.6% in white (Fisher's exact test, P < 0.001). KRAS is the second highest discrepancy gene in racial distribution. 11.6% Asian, 26.3% black, 27.3% of Native American had KRAS alteration in comparison to 36.1% in white (Fisher's exact test, P< 0.001). Conclusions: Our study demonstrated the potential diversity of genomic alterations across all racial groups with potential impact on therapeutic decisions.

3011 Background: Antibody blockade of semaphorin 4D (SEMA4D, CD100) promotes tumoral dendritic cell and CD8+ T cell infiltration and reduces function and recruitment of immunosuppressive myeloid cells. Importantly, these mechanisms to overcome immune exclusion and suppression have been shown to complement immune checkpoint therapies in preclinical models. Pepinemab is an IgG4 humanized monoclonal antibody targeting semaphorin 4D. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple T cell activation via checkpoint inhibition with beneficial modifications of the immune microenvironment via pepinemab. Methods: This phase 1b/2, single arm, first-in-human study is designed to evaluate the safety, tolerability and efficacy of pepinemab with avelumab in 62 patients (pts) with advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) pts and pts whose tumors progressed following immunotherapy (IOF). Results: Among 21 evaluable ION pts, 5 experienced partial response (PR), 3 pts had clinical benefit ≥ 1 year, and the disease control rate (DCR) is 81%. Pts enrolled in this study were observed to have lower PD-L1 expression relative to prior single agent studies (likely due to approval of pembrolizumab for first line therapy). We, therefore, performed subgroup analysis for response by PD-L1 status. The objective tumor response (ORR) in the PD-L1 negative and low population ( < 80% TPS by Dako 73-10 assay) appears to be approximately 2-2.5 fold greater with combination therapy than with historical single agent immune checkpoint controls. Notably, 97% of pts who experienced PR or SD were reported to have tumors with negative or low PD-L1 expression. Among 29 evaluable IOF pts, the combination resulted in 59% DCR, including 2 PR and 7 patients with durable clinical benefit of ≥ 23 weeks. Biomarker analysis of pre- and on-treatment biopsies confirmed increased CD8+ T cell density correlating with response. Surprisingly, analysis of myeloid-derived suppressor cells (MDSCs) revealed a relative paucity of these cells in pretreatment NSCLC biopsies as compared to other cancer indications such as HNSCC. Conclusions: This trial is nearing completion with only 5 of 62 subjects remaining on study. Preliminary data suggest the combination is well tolerated and shows signs of increased antitumor activity, particularly in PD-L1 negative or low tumors. Updated clinical response data and immunophenotypic analyses will be presented. Clinical trial information: NCT03268057 .

9058 Background: Lung Cancer is the leading cause of cancer related deaths in the USA. NSCLC comprises about 85% of lung cancer cases. Although timeliness of care in patients with NSCLC is considered an important aspect of quality care, there are conflicting data about its impact on clinical outcomes. The primary objective of this study is to determine if there is an association between TTI and survival in patients with NSCLC. Methods: In this retrospective study, we reviewed data from our multi-site Mayo Clinic Cancer Center registry and identified patients with newly diagnosed NSCLC from 2000 to 2016. TTI was calculated from time of diagnosis to time of first treatment (surgery, radiation therapy or systemic therapy). Analyses were performed by SAS software 9.4. Log-Rank test was used to compare survival. Cox regression multivariate model was used to evaluate the prognostic value of variables to survival. Results: 10010 patients (53% males and 47%) were reviewed. Median age at diagnosis was 70. Median TTI was 12 days for stage I, and 20 days for stage II, III and IV. We compared outcomes of patients with TTI > 20 days to TTI ≤20 days. Outcomes were stratified based on age, gender, grade, and stage. Median Overall Survival (OS) was significantly better for patients with TTI ≤20 days compared to TTI > 20 days (39.1 vs 28.6 months P-value < 0.0001). Further stratification, based on stage, showed significantly better OS for stage I and II patients with TTI ≤20 days compared to TTI > 20 days (103.4 vs. 63.9 months P-value < 0.0001 and 72.3 vs. 46.8 months P-value 0.0014 respectively). OS for stage III patients with TTI ≤20 days was not significantly different from patients with TTI > 20 days (30.6 vs. 28.5 months P-value 0.118). Interestingly, stage IV patients had worse OS if TTI ≤20 days compared to TTI > 20 days (8.3 vs. 12.8 months P-value < 0.0001). Conclusions: Our study showed an association between TTI and survival of patients with NSCLC. Shorter TTI was associated with better survival in stage I and II patients and worse survival in stage IV patients. Our study further highlights the controversy surrounding the topic of impact of timeliness of care on survival in patients with cancer, specifically NSCLC across different stages.

e20599 Background: The anti-PD-1 antibodies nivolumab and pembrolizumab have demonstrated improved overall survival (OS) and progression free survival (PFS) in a subset of patients with metastatic or locally advanced lung cancer (LC). To date, no blood biomarkers have been identified to predict clinical outcome to anti-PD-1 agents. Methods: A retrospective analysis of 52 patients with advanced LC and treated with anti-PD-1 antibodies in a single institution was performed. White blood cell count (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute neutrophil to absolute lymphocyte count ratio (ANC/ALC), absolute eosinophil count (AEC), and platelet counts at baseline before start of anti-PD-1 antibody were assessed. Kaplan–Meier and Cox regression analysis were done. Results: 48 patients were treated with nivolumab (92.3%) and 4 patients with pembrolizumab (7.7%). Median follow up was 13.6 months and median OS was 26 months. Higher baseline ANC and ANC/ALC ratio significantly correlated with worse clinical outcomes. Patients with baseline ANC > 6060/mm3 had a significantly increased risk of death [hazard ratio (HR) = 2.46; 95% CI 1.12–5.42, P = 0.025] and of progression on anti-PD-1 antibody [HR = 2.41; 95% CI 1.25–4.64, P = 0.009] compared with patients with ANC ≤6060/mm3. Similarly, patients with baseline ANC/ALC ratio ≥ 4.59 had a significantly increased risk of death [HR = 2.41; 95% CI 1.11–5.24, P = 0.027] and of progression on anti-PD-1 antibody [HR = 2.08; 95% CI 1.10–3.95, P = 0.027] compared with patients with ANC/ALC < 4.59. One year survival rate in patients who had ANC < 3390/mm3, ANC 3390-6060/mm3 and ANC > 6060/mm3 were 86.5%, 76.9% and 48.1% respectively. Conclusions: Increased baseline ANC and ANC/ALC were associated with poor PFS and OS in LC patients treated with anti-PD-1 antibodies. Although these findings need to be validated in a large sample size, our data suggested that baseline ANC and ANC/ALC ratio might help the risk stratification and assist treatment strategies. The potential predictive value of peripheral blood biomarkers for clinical outcomes to anti-PD-1 antibody should be further investigated in a prospective study.

3030 Background: Promising results in the treatment of NSCLC have been seen with agents targeting immune checkpoints, such as programmed cell death 1 (PD-1) or programmed cell death 1 ligand (PD-L1...