Citations

75 Background: 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, as well as durable tumor regression in preclinical models. Pepinemab (VX15/2503) is a first-in-class humanized monoclonal antibody targeting SEMA4D. Methods: The CLASSICAL-Lung clinical trial (NCT03268057) evaluates the combination of pepinemab with anti-PD-L1 antibody avelumab to couple beneficial modifications of the immune microenvironment via pepinemab with immune activation via checkpoint inhibition. This ongoing study evaluates the safety, tolerability and efficacy of the combination in patients with advanced (stage IIIB/IV) NSCLC, including immunotherapy-naïve (ION) patients and patients whose tumors progressed during or following immunotherapy (IOF). Results: The combination was well tolerated with no major safety signals identified. Among 29 evaluable IOF patients, two experienced confirmed partial response (PR) with 63% and 52% tumor reduction on study following acquired resistance to prior treatment with pembrolizumab, 15 additional patients experienced stable disease, and at least 5 patients with durable clinical benefit of ≥ 23 weeks. Among 21 evaluable ION patients, 5 experienced PR, clinical benefit ≥ 1 year was observed in 3 patients, and Disease Control Rate was 81%. Analysis of pre- and on-treatment biopsies demonstrated increased CD8+ T cell density correlating with response, reduction or elimination of tumor in 11/13 biopsies from subjects with PR or SD. Conclusions: Interim analysis suggests the combination of pepinemab plus avelumab is well tolerated and shows initial clinical signals of antitumor activity. Updated clinical response data (minimum of 6 mo. follow-up), as well as additional immunophenotyping of both inflammatory and suppressive myeloid cells will be presented. Clinical trial information: NCT03268057.

Abstract Background Immune-related adverse events (irAEs) have emerged as a serious clinical issue in the use of immune checkpoint inhibitors (ICIs). Risk factors for irAEs remain controversial. Therefore, we studied sex differences in irAEs in patients treated with anti-programmed cell death protein 1 (PD-1) therapy. Materials and Methods All patients with metastatic melanoma and non-small cell lung cancer (NSCLC) treated with anti-PD-1 therapy at Mayo Clinic Rochester and Florida from 2015 to 2018 were reviewed. Kaplan-Meier method and log-rank test was used for time-to-event analysis. Results In 245 patients with metastatic melanoma, premenopausal women were more likely to experience irAEs (all grades) compared with postmenopausal women and men (67% vs. 60% vs. 46%), primarily because of an increase in endocrinopathies (33% vs. 12% vs. 10%, respectively). In patients with NSCLC (231 patients), women (all ages) were also more likely to develop irAEs of all grades (48% vs. 31%). Women with NSCLC were more likely to develop pneumonitis (11% vs. 4%) and endocrinopathies (14% vs. 5%). No differences in grade ≥3 toxicities were seen across sexes in both cohorts, but women were more likely to receive systemic steroids for the treatment of irAEs compared with men. Better progression-free-survival was observed in women with NSCLC and irAEs (10 months vs. 3.3 months) compared with women without irAEs. Conclusion Women with metastatic melanoma and NSCLC are more likely to experience irAEs compared with men. We also observed differences between sexes in the frequency of certain irAEs. Larger studies are needed to investigate the mechanisms underlying these associations. Implications for Practice The results of this study suggest that women may be at a higher risk for immune-related adverse events (irAEs) compared with men when treated with anti-programmed cell death protein 1 therapy. In addition, women were more likely to develop certain irAEs, including endocrinopathies and pneumonitis. Close follow-up of women undergoing treatment with immune checkpoint inhibitors will allow clinicians to diagnose these treatment-related complications early, potentially reducing their associated morbidity and mortality. In addition, a possible association between irAEs and response to therapy was observed.

Abstract Purpose: Young age has been shown to be an independent predictor of poor outcome in breast cancer. In HER2-positive breast cancer, the effects of aging remain largely unknown. Experimental Design: A total of 4,547 patients were included [3,132 from North Central Cancer Treatment Group (NCCTG) N9831 and 1,415 from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31]. Pathologic stromal tumor-infiltrating lymphocyte (sTIL) and molecular tumor infiltrating lymphocyte (mTIL) signatures were evaluated. Results: In NCCTG N9831, comparable benefit of trastuzumab was observed in all patients [age ≤ 40; HR, 0.43; 95% confidence interval (CI), 0.28–0.66; P < 0.001; and age > 40; HR, 0.56; 95% CI, 0.45–0.69; P < 0.001]. Similar results were observed in NSABP B-31 (age ≤ 40; HR, 0.45; 95% CI, 0.29–0.68; P < 0.001; and age > 40; HR, 0.42; 95% CI, 0.33–0.54; P < 0.001). Among patients who received chemotherapy alone, younger age was associated with poor outcome in the hormone receptor–positive subset, but not the hormone receptor–negative subset, in both trials. Although there was no association between sTILs and age, a small, but significant increase in mTIL CD45 and some immune subset signatures were observed. Among patients who received chemotherapy alone, patients over 40 years of age with lymphocyte-predominant breast cancer had excellent outcome, with 95% remaining recurrence free at 15 years. Conclusions: Among patients treated with trastuzumab, there was no significant difference in outcome related to age. Our study suggests that trastuzumab can negate the poor prognosis associated with young age.

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.

Abstract Background Treatment of non‐small‐cell lung cancer (NSCLC) has been rapidly advancing over the last decade. Academic centers are considered equipped with better expertise. NSCLC outcome trends in novel therapeutic era and impact of initial treatment at academic centers have not been reported. Methods The National Cancer Database (NCDB) was used to identify NSCLC incident cases from 2004 to 2013. Overall survival (OS) was plotted by year of diagnosis and type of initial treatment center, accounting for several factors available in NCDB. Results A total of 1 150 722 NSCLC patients were included and separated by initial treatment center type (academic: 31.5%; nonacademic: 68.5%). Median follow‐up and OS for all patients were 11.8 months (range: 0‐133.6 months) and 13.1 months (95% CI: 13.08‐13.17), respectively. Median OS improved significantly for those diagnosed in 2010‐2013 (14.8 months [95% CI: 14.7‐14.9]) as compared to 2004‐2009 (12.4 months [95% CI: 12.3‐12.5]) ( P < 0.001). Treatment at academic centers was associated with improved OS (multivariate HR for OS = 0.929 [95% CI: 0.92‐0.94], P < 0.0010). Four‐year OS for academic and nonacademic cohorts was 28.5%% and 22.1%, respectively ( P < 0.001), and the difference was more pronounced in stage I to III NSCLC. Conclusion In this largest analysis, thus far, NSCLC survival has improved over time, and type of initial treatment center significantly influences survival. Identifying and removing barriers to obtaining initial treatment of NSCLC at academic medical centers could improve OS.

Abstract Background: In stage IV non-small cell lung cancer (NSCLC), survival has significantly improved with the use of novel therapies and better supportive care. Despite such trends, it has been noted that patients (pts) frequently refuse cancer treatment. Therefore, we explored the factors associated with treatment refusal in pts with stage IV NSCLC. Methods: Utilizing the National Cancer Database (NCDB), we identified all incident cases with stage IV NSCLC from 2004 to 2014. Patients who received cancer treatment outside of the reporting facility or died before receiving treatment were excluded. Multivariable logistic regression models were used to determine associations with treatment refusal. Results: A total of 341,993 pts were identified. On average, 5.4% of pts refused radiation therapy and 10.3% refused chemotherapy despite provider recommendations. The proportion of pts refusing radiation and chemotherapy increased over the study period from 4.2% to 7.3% and 7.9% to 15%, respectively (p&lt;0.001 for both). In multivariable analysis, men were less likely to refuse radiation or chemotherapy compared to women (OR: 0.82, 95%CI: 0.76-0.83, p&lt;0.001; OR: 0.84, 95%CI: 0.81-0.86, p&lt;0.001, respectively). Factors associated with radiation therapy refusal included: Medicaid or Medicare as primary insurance (OR: 1.95, 95%CI: 1.76-2.15, p&lt;0.001; OR: 1.25, 95%CI: 1.17-1.34, p&lt;0.001, respectively) or a &gt;2 Charlson Comorbidity Index (OR: 1.97, 95%CI: 1.85-2.10, p&lt;0.001). Moreover, receiving care at an academic center (OR: 0.57, 95%CI: 0.53-0.62, p&lt;0.001) was associated with less likelihood of refusing radiation. Regarding chemotherapy, uninsured pts (OR: 2.45, 95%CI: 2.26-2.66, p&lt;0.001), pts with Medicaid as primary insurance (OR: 2.17, 95%CI: 2.03-2.32, p&lt;0.001) or with a high comorbidity index (OR: 1.76, 95%CI: 1.68-1.84, p&lt;0.001) were more likely to refuse chemotherapy. Contrary to findings from previous studies, Non-Hispanic Blacks and Hispanics were less likely to refuse chemotherapy compared to non-Hispanic whites (OR: 0.86, 95%CI: 0.82-0.91, p&lt;0.001; OR: 0.78, 95%CI: 0.72-0.89, p&lt;0.001). Patients receiving care at an academic center and residing in high income neighborhoods were less likely to refuse chemotherapy (OR: 0.76, 95%CI: 0.72-0.80, p&lt;0.001; OR: 0.76, 95%CI: 0.71-0.81, p&lt;0.001, respectively). Distance from residence to treating facility and living in a rural county did not affect treatment refusal. Conclusions: Socioeconomic factors rather than race/ethnicity appear to influence refusal of cancer treatment in pts with stage IV NSCLC in the NCDB. Assessing socioeconomic challenges should be an essential part of patients' evaluation when discussing treatment options. Citation Format: Narjust Duma, Urshila Durani, Ryan Frank, Jonas Paludo, Gustavo Westin, Yanyan Lou, Leventakos Konstantinos, Julian Molina, Ronald Go, Aaron Mansfield, Sikander Ailawadhi, Alex Adjei. Influence of sociodemographic factors on treatment decisions in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4230.