Lou, Yanyan

Abstract Purpose: The CLASSICAL-Lung clinical trial tested the combination of pepinemab, an IgG4 humanized mAb targeting semaphorin 4D, with the PD-L1 inhibitor avelumab to assess the effects of coupling increased T-cell infiltration and reversal of immune suppression via pepinemab with sustained T-cell activation via checkpoint inhibition. Patients and Methods: This phase Ib/II, single-arm study was designed to evaluate the safety, tolerability, and efficacy of pepinemab in combination with avelumab in 62 patients with advanced non–small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) patients and patients whose tumors progressed following anti-PD-1/L1 monotherapy (IOF). The main objectives were to evaluate safety/tolerability, establish a recommended phase 2 dose (RP2D), obtain a preliminary evaluation of antitumor activity, and investigate candidate biomarker activity. Results: The combination was well tolerated with no major safety signals identified. Pepinemab, 10 mg/kg with avelumab, 10 mg/kg, every 2 weeks, was selected as the RP2D. Among 21 evaluable ION patients, 5 patients experienced partial responses (PR), 4 patients evidenced clinical benefit ≥1 year, and the disease control rate (DCR) was 81%. Notably, overall response rate with the combination therapy was higher than previously reported for single-agent avelumab in the PD-L1-negative/low population. Among 29 evaluable IOF patients, the combination resulted in a DCR of 59%, including 2 PR and 7 patients with durable clinical benefit of ≥23 weeks. Biomarker analysis of biopsies demonstrated increased CD8 T-cell density correlating with RECIST response criteria. Conclusions: The combination of pepinemab with avelumab was well tolerated in NSCLC and showed signs of antitumor activity in immunotherapy-resistant and PD-L1-negative/low tumors.

Abstract Background Accumulated evidence supports the existence of sex-associated differences in immune systems. Understanding the role of sex in immune-related adverse events (irAEs) is important for management of irAE in patients receiving immunotherapy. Methods We performed meta-analysis on published clinical study data and multivariable logistic regression on pharmacovigilance data and applied a propensity algorithm to The Cancer Genome Atlas omics data. We further validated our observations in 2 independent in-house cohorts of 179 and 767 cancer patients treated with immune checkpoint inhibitors. Results A meta-analysis using 13 clinical studies that reported on 1096 female patients (36.8%, 95% confidence interval [CI] = 35.0% to 38.5%) and 1886 male patients (63.2%, 95% CI = 61.5% to 65.0%) demonstrated no statistically significant irAE risk difference between the sexes (odds ratio [OR] = 1.19, 95% CI = 0.91 to 1.54, 2-sided P = .21). Multivariable logistic regression analysis of 12 225 patients from the Food and drug administration Adverse Event Reporting System (FAERS) and 10 979 patients from VigiBase showed no statistically significant difference in irAEs by sex. A propensity score algorithm used on multi-omics data for 6019 patients from The Cancer Genome Atlas found no statistically significant difference by sex for irAE-related factors or pathways. The retrospective analysis of 2 in-house patient cohorts validated these results (OR = 1.55, 95% CI = 0.98 to 2.47, false discovery rate = 0.13, for cohort 1; OR = 1.16, 95% CI = 0.86 to 1.57, false discovery rate = 0.39, for cohort 2). Conclusions We observed minimal sex-associated differences in irAEs among cancer patients who received immune checkpoint inhibitor therapy. It may be unnecessary to consider sex effects for irAE management in clinical practice.

Introduction Immune-mediated hematologic disorders are relatively rare but potentially life-threatening immune-related adverse events (irAE) with immune checkpoint inhibitor (ICI) therapy (Shiuan, Beckermann et al 2017). The management strategy often relies on systemic corticosteroids and other immunosuppressant agents in steroid-refractory cases (Brahmer, Lacchetti et al 2018). We hereby describe our institution's experience in diagnosing and managing immune-related hematologic adverse events (ir-h-AE). Methods We retrospectively searched the electronic health record for all ir-h-AE diagnosed by treating providers and confirmed by study authors between 2015 and 2020. The search included patients on ICI and the following conditions: immune-related neutropenia (IRN), autoimmune hemolytic anemia (AIHA), cold agglutinin disease (CAD), immune thrombocytopenia (ITP), immune-related pancytopenia, aplastic anemia (AA), and pure red cell aplasia (PRCA). For AIHA, PRCA, and CAD, partial response (PR) was defined as hemoglobin greater than 10 g/dL but < 12 g/dL and 2 g/dL above the nadir without blood product transfusion. Complete response (CR) was defined as hemoglobin of ≥ 12 g/dL and 2 g/dL above the nadir without blood product transfusion (Peñalver, Alvarez-Larrán et al. 2010). For ITP, CR was defined as platelet count ≥ 100 × 109/L and absence of bleeding. PR was defined as platelet count ≥ 30 × 109/L and ≥ two-fold increase from the baseline count and absence of bleeding (Gómez-Almaguer, Tarín-Arzaga et al. 2013). For IRN, CR was defined as absolute neutrophil count (ANC) ≥ 1500/ mm3 on 2 consecutive measurements separated by 7 days; PR was defined as ANC ≥ 500/ mm3 sustained over 7 days. JMP® 14.1 was used for data analysis. Results Seventeen patients were identified, 9 (52.9%) of whom were female (table 1). Median age was 68 years (range 26-78). The most common pre-existing malignancies were melanoma (6 patients, 35.3%), non-small cell lung cancer (4 patients, 23.5%), and gastrointestinal cancer (3 patients, 17.6%). The ir-h-AE included 7 patients (41.2%) with warm AIHA, 4 (23.5%) with ITP (1 had immune-related pancytopenia that resolved with ITP persisting), 3 (17.6%) with IRN, 1 with AA, 1 with CAD, and 1 with PRCA and mild ITP. All patients had received an ICI dose within 60 days of diagnosis (range 3-52 days, median 18 days). Only 1 patient had a concomitant chronic autoimmune disorder (antinuclear antibody-positive arthritis). Four patients (23.5%) were receiving chemotherapy. Sixteen patients (94.1%) required treatment and received corticosteroids. Eight out of 15 evaluable patients (53.3%) responded to corticosteroids only. Another 4 responders (26.7%) required additional therapies including intravenous immunoglobulins (IVIG) (4, 23.5%) and/or rituximab (4, 23.5%). Overall response rate was 71.4% for AIHA and 100% for IRN. ITP was likely underrepresented in our cohort, and the response rate of 66.7% is likely lower than the response rate in clinical practice. This could be related to the fact that many mild thrombocytopenia cases are not further evaluated in clinical practice. None of our patients died from the sequelae of an ir-h-AE. Two patients (11.8%) died within 30 days of ir-h-AE diagnosis (disseminated intravascular coagulation likely due to the underlying malignancy and sepsis from bacterial pneumonia). At the time of ir-h-AE diagnosis, the malignancy was showing evidence of response in 9 patients (52.9%), progression in 6 patients (35.3%), and stability in 2 patients (11.8%). ICI therapy was permanently discontinued in 9 patients (52.9%) and temporarily held in 6 patients (35.3%). Three of the 5 patients (60%), who were rechallenged with ICI therapy, had recurrence of the same ir-h-AE (AIHA) with adequate response to therapy. Non-hematologic irAE (7 patients, 41.2%) included 3 patients with hepatitis, 2 with thyroiditis, 2 with pneumonitis, 1 with colitis, and 1 with dermatitis. Conclusion Our clinical experience with ir-h-AE highlights the importance of exercising vigilance in assessing the hematologic parameters of patients receiving ICI therapy. While relatively rare, ir-h-AE may impact the clinical course of patients with cancer and their eligibility for therapies that have the potential of offering durable control of the underlying malignancy. ir-h-AE respond to classical therapies including corticosteroids, IVIG, and rituximab. Disclosures Block: Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Marker Therapeutics: Research Funding; Transgene: Research Funding; Immune Design: Research Funding. Kottschade:Bristol-Myers Squibb: Consultancy, Research Funding.

With the advent of targeted therapy for non-small-cell lung cancer, there are many new available treatment options for patients whose cancer harbors an actionable mutation or alteration. These new medications come with numerous side effects, for some of which, the management is not well defined. Alectinib is a second-generation tyrosine kinase inhibitor approved for stage-IV lung adenocarcinoma with anaplastic lymphoma kinase gene rearrangement. Severe (⩾Grade 3) skin rash is a rare side effect of alectinib. Reintroducing alectinib in patients with severe skin rash is not well defined in the medical literature. While other case reports have outlined their approach and desensitization protocol, the maximum dose that patients were titrated up to in a desensitization protocol was 300 mg twice daily. Here, we report a case of Grade 3 skin rash secondary to alectinib, and our experience in managing the rash and reintroducing alectinib with a unique desensitization protocol to a max of 600 mg twice daily (full dose). This case could provide further guidance to oncologists managing patients with this adverse event and may aid in reducing concerns to both patients and physicians about recurrence of skin rash at the maximum dose.

Abstract Despite progress of immune checkpoint therapies, many cases of non-small cell lung cancer (NSCLC) are refractory or acquire resistance to current therapies. Antibody blockade of semaphorin 4D (SEMA4D, CD100) can overcome resistance mechanisms of immune exclusion and myeloid suppression. Importantly, combinations of anti-SEMA4D with various immunotherapies enhanced T cell infiltration and activity, leading to durable tumor regression in preclinical models. Pepinemab (VX15/2503) is a first-in-class humanized monoclonal antibody targeting SEMA4D. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple immune activation via checkpoint inhibition with beneficial modifications of the tumor immune microenvironment via pepinemab. Here, we present interim results of the Phase 2 portion of the CLASSICAL-Lung study. This phase 1b/2, open label, single arm, first-in-human combination study is designed to evaluate the safety, tolerability and efficacy of pepinemab in combination with avelumab in 62 subjects with advanced stage (IIIB/IV) NSCLC, including immunotherapy-naïve (ION) patients and patients whose tumors progressed during or following immunotherapy (IOF). Dose escalation was successfully completed, presented previously, and no concerning safety signals have been identified to date. Among 29 evaluable IOF patients, 2 experienced confirmed partial response (PR) with 66% and 52% tumor reduction following acquired resistance to prior treatment with pembrolizumab, 15 additional patients experienced stable disease (SD), and at least 7 patients had durable clinical benefit of ≥ 23 weeks. Among 21 evaluable ION patients, 5 experienced PR, and 3 patients had clinical benefit ≥ 1 year. The disease control rate was 81%. Analysis of pre- and on-treatment biopsies demonstrated increased CD8+ T cell density correlating with response, with reduction or elimination of tumor in 10/11 biopsies from subjects with PR or SD. It was notable that 79% of patients who experienced PR or SD were reported to have tumors with negative or low PD-L1 expression. Enrollment is complete and this interim analysis suggest the combination of pepinemab plus avelumab is well tolerated and shows initial clinical signals of antitumor activity. Updated clinical response data, as well as additional immunophenotyping of both inflammatory and suppressive myeloid cells will be presented. Citation Format: Jonathan W. Goldman, Terrence L. Fisher, Elizabeth Evans, John E. Leonard, Desa Rae Pastore, Crystal Mallow, Ernest Smith, Andreas Schröeder, Kevin Chin, Michael Shafique, Thaddeus Beck, Megan A. Baumgart, Ramaswamy Govindan, Nashat Gabrail, Rachel E. Sanborn, Alexander I. Spira, Nagashree Seetharamu, Yanyan Lou, Aaron S. Mansfield, Maurice Zauderer. Interim results from CLASSICAL-Lung, phase 1b/2 study of pepinemab (VX15/2503) in combination with avelumab in advanced NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT191.

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.