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Ara A Vaporciyan



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    MA06 - Challenges in the Treatment of Early Stage NSCLC (ID 124)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      MA06.10 - Stereotactic Ablative Radiotherapy in the Management of Synchronous Early Stage Non-Small Cell Lung Cancers (Now Available) (ID 1924)

      13:30 - 15:00  |  Author(s): Ara A Vaporciyan

      • Abstract
      • Presentation
      • Slides

      Background

      The aim of the study is to evaluate the efficacy and patterns of failure of early stage synchronous non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR).

      Method

      Patients with synchronous NSCLC who received SABR (50 grays in 4 fractions or 70 grays in 10 fractions) to at least one lesion were reviewed. Synchronous lesions were defined as multiple ipsilateral or contralateral intrapulmonary lesions diagnosed within 6 months.

      Result

      Out of a total of 912 patients treated with SABR for early stage NSCLC between 2005 and 2015, 82 (9%) had synchronous disease. The median age was 70 years and 34 (41.5 %) patients were males. The median diameter was 2.1 cm (Interquartile range (IQR) 1.6-3 cm) for index lesions and 1.5 cm (IQR 1.1-2.2 cm) for second lesions. At a median follow-up time of 58 months, the 1, 3 and 5-year progression-free survival (PFS) rates were 85.4%, 47.3% and 28.5%, respectively; the corresponding overall survival rates were 95.1%, 66.9% and 52.4% and the 1, 3 and 5-year local recurrence (LR)-free survival rates were 97.3%, 79.6% and 70.8%, respectively. Among the 39 (47.6%) patients with disease progression, intralobal LR was the first site of failure in 15 (18.3%) patients, with a total of 19 local recurrences out of 169 (11.2%) thoracic lesions. Isolated regional recurrence occurred in 3 (3.7%) patients, and distant failure in 221 (25.6%) patients. On multivariate analysis, factors associated with improved PFS were an improved ECOG PS score (HR 10.786; 95% CI 2.845-40.902; p-value <0.001), DLCO (HR 0.947; 95% CI 0.903-0.994; p-value 0.026) and an index lesion pathology of adenocarcinoma (HR 0.167; 95% CI 0.033-0.841; p-value 0.030). Only the ECOG PS score maintained significance (HR 6.165; 95% CI 2.081-18.263; p-value 0.001) on multivariate analysis for OS. No association was found between the use of chemotherapy as part of the initial management strategy and survival outcomes. Similarly, no difference in outcomes was observed whether all lesions were treated with SABR compared to SABR and other modalities.

      Conclusion

      SABR achieves promising long-term survival and tumor control rates and may be a potential curative treatment for synchronous early stage NSCLC. Our data indicates that patients presenting with synchronous NSCLC lesions can be approached as having two separate primary lung tumors, and be offered definitive local therapy with aims of cure.

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    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA11.09 - Increased Frequency of Bystander T Cells in the Lungs Is Associated with Recurrence in Localized Non-Small Cell Lung Cancer (Now Available) (ID 955)

      14:00 - 15:30  |  Author(s): Ara A Vaporciyan

      • Abstract
      • Presentation
      • Slides

      Background

      Non-small cell lung cancer (NSCLC) exhibits a high mutational burden. As a result, patients afflicted by this tumor type experience greater responses to immune checkpoint blockade. This is largely due to the ability of T cells to destroy tumor cells on the basis of antigens recognized by their T cell receptor (TCR). However, the lungs are exposed to carcinogens and pathogens which can also trigger a T cell response distinct from cancer. Therefore, a better understanding of the T cell repertoire in the lungs is needed to improve upon the success of current immunotherapies in NSCLC.

      Method

      We obtained peripheral blood, tumors, and adjacent uninvolved lungs from a cohort of 236 early stage NSCLC patients. Whole exome sequencing, RNA microarray, immunohistochemistry (CD3, CD4, CD8, CD57, CD68, FoxP3, CD45RO, GzmB, PD-1, and PD-L1) and T cell repertoire sequencing were performed in NSCLC patients and lungs from organ donors and COPD patients. Antigen specificity was predicted using the Grouping of Lymphocyte Interactions by Paratope Hotspot (GLIPH) algorithm. Single cell TCR and RNA sequencing as well as sequencing of the virome are underway.

      Result

      Clonality was associated with CD8 T cells (r=0.31; p=0.0003), GzmB (r=0.29; p=0.001) and IFN-γ (r=0.52; p<0.0001) production as well as with tumor mutational burden (r=0.19; p=0.015), HLA-B (r=0.29; p=0.0005) and β2-m expression (r=0.20; p=0.018). Patients with classical EGFR mutations exhibited lower T cell clonality (p=0.003) even after adjustment for TMB, highlighting the impact of this driver mutation on the T cell response. Surprisingly, clonality was higher in the adjacent uninvolved lung than tumor (p<0.0001), suggesting an active antigenic response outside the tumor. Comparison of the composition of the T cell repertoire between the uninvolved lung and tumor revealed 57% of the top 100 T cells in the tumor were also found in the adjacent normal lung, highlighting certain parallels in the ongoing antigenic responses. Deeper analysis suggested that shared T cells may have been reactive against mutations shared between the normal lung and tumor (r=0.23, p=0.028) or viruses (p<0.0001). Accordingly, patients with a more reactive T cell repertoire outside the tumor (i.e. bystanders) exhibited shorter disease-free survival (p=0.036) suggesting these responses against shared mutations and/or viruses may detract from the anti-tumor T cell response.

      Conclusion

      Our findings highlight the importance of understanding the specificity of the T cell repertoire in the lungs in patients with NSCLC treated with immunotherapy. As a high proportion of bystander T cells appear to reside in the lungs, their reactivation could contribute to the impaired responses and/or increased toxicity observed in certain patients with NSCLC treated with immunotherapy.

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    OA13 - Ideal Approach to Lung Resection and Novel Perioperative Therapy (ID 146)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      OA13.06 - Surgical Outcomes Following Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Non-Small Cell Lung Cancer - NEOSTAR Study (Now Available) (ID 2041)

      11:30 - 13:00  |  Author(s): Ara A Vaporciyan

      • Abstract
      • Presentation
      • Slides

      Background

      Surgical outcomes following neoadjuvant immune checkpoint inhibitors (ICIs) are limited. We report 90-day perioperative results of the NEOSTAR phase II trial of neoadjuvant nivolumab or nivolumab/ipilimumab in resectable non-small cell lung cancers (NSCLCs).

      Method

      44 pts with stage I-IIIA NSCLC (AJCC 7th) were randomized to nivolumab (3 mg/kg IV, days 1, 15, 29, n=23) or nivolumab/ipilimumab (1 mg/kg IV, day 1, n=21) with resection planned between 3-6 weeks after last dose. Surgical approach and extent of resection were at surgeons’ discretion.

      Result

      39 (89%) patients underwent R0 resection, of those 2 (5%) were resected off trial after additional induction chemotherapy (1 nivolumab, 1 nivolumab/ipilimumab). Among 37 patients, 21 underwent surgery following nivolumab and 16 following nivolumab/ipilimumab. Median age 66 (43-83) years, 24 (65%) male, 33 (89%) white, 22 (59%) adenocarcinoma, 22 (59%) stage I, 9 (24%) stage II, 6 (16%) stage IIIA.

      5 (11%) were not resected, 1 (1/23, 4%) after nivolumab (stage II), 4 (4/21, 19%) after nivolumab/ipilimumab (1 stage I, 1 stage II, 2 stage IIIA). Reasons for unresectability were change in surgeon’s judgement (n=2), toxicity (n=1), progression (n=1), and declining pneumonectomy (n=1). Median time to surgery was 31 days (range 21-87). 8 (22%) operations were delayed beyond 42 days, 5 after nivolumab/ipilimumab (5/16, 31%) and 3 after nivolumab (3/21, 14%).

      33 (89%) underwent lobectomy, 2 (5%) pneumonectomy, 1 (3%) segmentectomy and 1 (3%) wedge resection. 27 (73%) had thoracotomy, 7 (19%) thoracoscopy, 3 (8%) robotic approach. 2 (5%) were electively converted from thoracoscopy to thoracotomy. Median operative time was 147 minutes (71-315), median blood loss was 100cc (50-1000), and median length of stay was 4 days (1-18).

      Perioperatively, pulmonary complications occurred in 8 (22%) patients: 8 (22%) prolonged air leak, 2 (5%) pneumonitis/pneumonias, 1 (3%) empyema, and 1 (3%) bronchopleural fistula (BPF). 1 (3%) died from complications of BPF and steroid therapy for pneumonitis. 4 (11%) developed atrial fibrillation, 1 (3%) diarrhea, 1 (3%) ileus, and 1 (3%) transient ischemic attack.

      Surgeons subjectively judged 15/37 (40%) of operations to be more complex than usual with 7/37 (19%) lasting > 4 hours.

      Conclusion

      Following three cycles of neoadjuvant ICIs 89% of patients underwent complete R0 resection, including two patients who received additional induction chemotherapy off trial. Five marginally operable patients who didn’t proceed to resection, and one perioperative mortality highlight the importance of cautious patient selection for neoadjuvant ICIs in the management of operable NSCLC.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-79 - CD73 Expression in Lung Adenocarcinomas and Immunological and Molecular Associations (ID 2412)

      09:45 - 18:00  |  Author(s): Ara A Vaporciyan

      • Abstract

      Background

      Immune checkpoints inhibitors (ICI), in monotherapy or combination with chemotherapy, are the standard of care for lung adenocarcinoma (ADC) patients. Unfortunately, only a restricted number of patients will respond to ICI. Combination therapies such as CD73 inhibitors, are being studied with the goal to achieve synergic effects. CD73 is a membrane-bound protein with immunosuppressive functions. We previously reported that higher immune cell infiltration was associated mainly to CD73 basolateral (BL) expression, in this abstract, we show the correlation of CD73 expression at luminal (L) and BL membrane of ADC malignant cells (MCs), with annotated clinicopathological characteristics, immune and molecular biomarkers.

      Method

      CD73 IHC expression (clone D7F9A) was evaluated in 106 archived ADCs from patients that underwent surgical treatment without neoadjuvant therapy between February 1999 and February 2012 at MD Anderson Cancer Center (Houston, Texas, USA). We scored % and H-score of CD73 expression at the luminal (L) and basolateral (BL) membrane, we calculated the Total (T) CD73 as the average of L and BL, and classified ADCs in three groups: ‘T High’ (TH) (upper quartile for all tumors); ‘T Low’ (TL); ‘T Neg’ (TN) (<1%). We correlated T, L and BL expression and the three groups with clinicopathological characteristics, mutational status of KRAS and EGFR, TP53, STK11 and Tumor mutation burden (TMB), and cell densities of CD3, CD8, CD68, CD45RO, FOXP3, and Granzyme B, and PD-L1 expression (clone E1L3N) in MCs.

      Result

      T CD73 expression was found in 76%; BL in 60% and L in 57%; among ADCs with luminal membrane present (n=72), L CD73 was present in 83%. T+ and L+ expression was more frequent in never smokers (p=0.02 and p=0.003). Also higher frequency of L+ was found in older patients (>65) (p=0.01), tumors with non-solid histology patterns (p<0.001), EGFR mutation (p=0.048), non-mutated p53 (p=0.002), negative PD-L1 (p=0.03), and low TMB (<10 mut/MB) (p=0.001). Higher levels of L expression were found in KRAS mutated tumors (p=0.049). Higher BL expression positively correlated with p53 mutated tumors (p=0.038), PD-L1+ in MCs (p=<0.0001), and higher TMB (p=0.040).

      Our group analyses revealed that TH and TN were associated with ADCs from patients with >30 pack-year of smoking history (p=0.04), presence of any-solid histology pattern (p=0.03), p53 mutation (p= 0.005) and higher TMB (p=0.003) compared with TL. TH also had higher frequency of PD-L1+ tumors, and a higher cell density of CD3 (p=0.0001), CD8 (p=0.001), CD68 (p=0.048), CD45RO (p=0.036), FOXP3 (p=0.053), and Granzyme B (p=0.024) compared to TL and TN. TN showed higher frequency of STK11 mutation (p=0.034).

      Conclusion

      Based on the CD73 expression we defined subsets of lung adenocarcinomas that have distinct histological, molecular and immunological characteristics that may play a role in the response to ICI.

      Our characterization could help us to understand patient’s response to ICI, and identify patients that could potentially benefit from combination therapies.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-90 - Nodal Immune Flare (NIF) Following Neoadjuvant Anti-PD-1 and Anti-CTLA-4 Therapy in Non-Small Cell Lung Cancer   (Now Available) (ID 2065)

      10:15 - 18:15  |  Author(s): Ara A Vaporciyan

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors (ICIs) have induced durable responses in selected non-small cell lung cancer (NSCLC) patients. However, ICIs have also shown to induce tumor pseudo-progression in some cases. We report the incidence and consequences of a distinct phenomenon – the apparent radiographic progression of lymph nodes without pathological evidence of tumor – that we define “nodal immune flare” (NIF), following neoadjuvant ICIs in the NEOSTAR phase 2 trial of nivolumab or nivolumab plus ipilimumab for operable NSCLCs.

      Method

      NEOSTAR randomized 44 patients with stage I-IIIA (AJCC 7th edition) to nivolumab (3 mg/kg IV, days 1, 15, 29) or nivolumab/ipilimumab (1 mg/kg IV, day 1) with planned surgery between 3-6 weeks after last dose. Computed tomography (CT) and positron emission tomography (PET-CT) were obtained prior to ICIs and prior to resection. Response Evaluation Criteria in Solid Tumors v1.1 were used to evaluate responses.

      Result

      44 patients, median age 66 years (range 43-83), 28 (64%) males, 37 (84%) white were randomized to nivolumab (n=23) or nivolumab/ipilimumab (n=21). 26 (59%) had adenocarcinoma, 17 (39%) squamous cell, 1 (2%) adenosquamous carcinoma. 23 (52%) stage I, 12 (27%) stage II, 9 (20%) stage IIIA. 39 (89%) underwent complete resection, 2 off trial, and 5 (11%) were not resected.

      NIF occurred in 5/44 (11%) patients, 3 post nivolumab (3/23, 13%) and 2 (2/21, 10%) post nivolumab/ipilimumab. All patients had no evidence of malignancy in nodes of interest prior to ICIs. 2 (2/26, 8%) occurred in adenocarcinoma and 3 (3/17, 18%) in squamous cell. 2 (5%) required additional invasive restaging, 3 (7%) change in surgical plan, 1 (2%) declined surgery, 1 (2%) was thought to have disease progression and was treated with chemotherapy plus ICI prior to resection off study, and 1 (2%) underwent planned resection. Pathologic evaluation of the flared nodes revealed no evidence of cancer in all 5 patients, rather demonstrated noncaseating granulomata.

      In a previous neoadjuvant trial utilizing platinum-based chemotherapy with nintedanib, we did not observe NIF in 21 patients in absence of pathologic evidence of tumor progression (primary or nodal metastases).

      Conclusion

      NIF occurred in 11% of patients following neoadjuvant ICIs and changed treatment plan in 9% of patients. This is the first preliminary report of NIF in operable NSCLCs treated with neoadjuvant single and combined ICIs. Considering the number of ongoing neoadjuvant immunotherapy trials, we highlight the importance of judicious and invasive restaging of sites of suspected progression after neoadjuvant ICIs prior to definitive treatment decisions.

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