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Lecia Sequist

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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: 12
    • Now Available
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      MA11.01 - Multifactorial Model to Predict Response to PD-(L)1 Blockade in Patients with High PD-L1 Metastatic Non-Small Cell Lung Cancer (Now Available) (ID 2322)

      14:00 - 15:30  |  Presenting Author(s): Kathryn C. Arbour  |  Author(s): Miruna Oprescu, Joe Hakim, Hira Rizvi, Mark Leiserson, Michelle Ginsburg, Andrew J. Plodkowski, Jennifer Sauter, Isabel Preeshagul, Sharon Gillett, Philip Rosenfield, Lester Mackey, Miroslav Dudik, Matthew Hellmann

      • Abstract
      • Presentation
      • Slides

      Background

      High PD-L1 expression (≥50%) is a routine biomarker but is incompletely predictive, with response rates to PD-1 monotherapy only 35-45% in patients with lung cancer. Beyond PD-L1, additional individual pre-treatment variables, including clinical (smoking history, BMI), genomic (TMB, STK11, EGFR), and laboratory features (baseline dNLR), individually associate with response but have not been comprehensively examined in combination. We hypothesized that a multifactorial model incorporating routinely available clinical, pathologic, and genomic variables could improve prediction of response in high PD-L1 patients receiving first line anti-PD-(L)1 monotherapy.

      Method

      190 patients from MSKCC with advanced, PD-L1 high NSCLC (PD-L1 ≥50%) treated with PD-1 or PD-L1 inhibitor were identified and separated into training (n=134, 70%) and validation cohorts (n=56, 30%). In addition to PD-L1 expression, 39 variables were collected, including histology, clinical (age, gender, performance status, smoking, clinical trial vs standard of care treatment), molecular (TMB, EGFR, KRAS, STK11, KEAP1, TP53, ALK, ROS1, BRAF), and baseline CBC (including dNLR). Radiologic response assessments were performed according to RECIST 1.1. To distinguish responders vs. non-responders, a logistic regression classifier with an elastic net penalty was used to restrict the number of variables considered and to optimize generalizability to independent cohorts. The parameters of the model were optimized using only the training cohort and its performance was measured on the validation cohort.

      Result

      In PD-L1 high NSCLC patients treated with PD-(L)1 blockade, the ORR was 43%. In the training cohort, 5 features (PD-L1 expression, current smoking status, lymphocyte count, platelets, total WBC) associated with response . Three features (EGFR mutation, STK11 mutation, standard of care treatment) associated with lack of response. TMB was not predictive within this selected PD-L1 high cohort. In the training cohort, the eight identified features were used to develop a multifactorial model which improved BOR prediction (AUC 0.83) compared to PD-L1 alone (AUC 0.65), p=0.02. Improved performance of the model was confirmed in the validation cohort (AUC 0.66 for multifactorial model vs. AUC 0.52 for PD-L1 alone).

      Conclusion

      Among patients with high PD-L1 expression, multiple clinical, molecular, and baseline laboratory features impact response to PD-(L)1 monotherapy. The addition of these routinely available variables to PD-L1 in a multifactorial model improves prediction of response to PD-(L)1 blockade in patients with high PD-L1. This approach may help further stratify patients within the PD-L1 high population and identify which patients are likely to benefit from PD-(L)1 monotherapy vs those who should consider chemotherapy + immunotherapy.

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      MA11.02 - KEYNOTE-042 China Study: First-Line Pembrolizumab vs Chemotherapy in Chinese Patients with Advanced NSCLC with PD-L1 TPS ≥1% (Now Available) (ID 1772)

      14:00 - 15:30  |  Presenting Author(s): Yi-Long Wu  |  Author(s): Li Zhang, Yun Fan, Jianying Zhou, Li Zhang, Qing Zhou, Wei Li, ChengPing Hu, Gongyan Chen, Xin Zhang, Caicun Zhou, Thao Dang, Justina Penrod, Debra A. Kush, Yun Qin, Ben Li, Tony Mok

      • Abstract
      • Presentation
      • Slides

      Background

      In the global, open-label KEYNOTE-042 study (NCT02220894), pembrolizumab significantly improved OS vs chemotherapy in PD-L1–positive locally advanced/metastatic NSCLC without targetable EGFR/ALK aberrations (HRs: TPS ≥50%, 0.69; ≥20%, 0.77; and ≥1%, 0.81). We present the very first results for Chinese patients enrolled in the KEYNOTE-042 global and China extension (NCT03850444) studies.

      Method

      The global and extension studies were designed identically. Patients were randomized 1:1 (stratified by ECOG PS 0/1, squamous/nonsquamous histology, and TPS ≥50%/1‒49%) to up to 35 cycles of pembrolizumab 200 mg Q3W or up to 6 cycles of paclitaxel/pemetrexed + carboplatin with optional pemetrexed maintenance (nonsquamous only). Primary endpoints were OS in patients with PD-L1 TPS ≥50%, ≥20%, and ≥1%. No alpha was allocated to the China extension analysis. Overall, ~350 patients from China will be enrolled including 140 patients with TPS ≥50%, to determine the OS effect of pembrolizumab and consistency across outcomes in Chinese patients.

      Result

      As of September 4, 2018, 262 Chinese patients with PD-L1–positive (TPS ≥1%) NSCLC were enrolled (global, n=92; China extension, n=170) and randomized to pembrolizumab (n=128) or chemotherapy (n=134). 146 patients (55.7%) had PD-L1 TPS ≥50%; 204 (77.9%) had PD-L1 TPS ≥20%. After median (range) follow-up of 11.3 (0.1‒23.2) months, 32 patients (25.0%) were still receiving pembrolizumab and 6 (4.8%) were receiving pemetrexed maintenance. Pembrolizumab improved OS vs chemotherapy in patients with PD-L1 TPS ≥50%, ≥20%, and ≥1% (Table). Among patients who received ≥1 dose of pembrolizumab (n=128) or chemotherapy (n=125), grade 3–5 drug-related AEs occurred in 17% vs 68%, respectively.

      Overall Survival

      n

      Median (95% CI), mo

      HR (95% CI)

      PD-L1 TPS ≥50%

      Pembrolizumab

      72

      20.0 (15.5–NR)

      0.62 (0.38–1.00)

      Chemotherapy

      74

      14.0 (10.0–17.9)

      PD-L1 TPS ≥20%

      Pembrolizumab

      101

      20.0 (17.4–NR)

      0.62 (0.41–0.95)

      Chemotherapy

      103

      13.7 (10.1–17.9)

      PD-L1 TPS ≥1%

      Pembrolizumab

      128

      20.0 (17.4–NR)

      0.65 (0.45–0.94)

      Chemotherapy

      134

      13.7 (10.1–17.9)

      PD-L1 TPS 1–49%a

      Pembrolizumab

      56

      19.9 (11.9–NR)

      0.69 (0.40–1.20)

      Chemotherapy

      60

      10.7 (8.3–20.9)

      NR, not reached. aExploratory analysis.

      Conclusion

      Pembrolizumab monotherapy improved OS with a favorable safety profile vs platinum-based chemotherapy as first-line therapy in Chinese patients with locally advanced/metastatic NSCLC without sensitizing EGFR/ALK aberrations and a PD-L1 TPS ≥1%. Findings are consistent with the global study primary endpoints, supporting first-line use of pembrolizumab for PD-L1–expressing advanced/metastatic NSCLC in China.

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      MA11.03 - Pembrolizumab Plus Docetaxel Increases Progression-Free Survival Compared with Docetaxel Alone in Previously Treated Advanced Non-Small Cell Lung Cancer Patients (Now Available) (ID 2017)

      14:00 - 15:30  |  Presenting Author(s): Oscar Gerardo Arrieta  |  Author(s): Feliciano Barrón, Amir Carmona, Laura Alejandra Ramírez-Tirado, Zyanya Lucia Zatarain Barrón, Andrés Felipe Cardona, Yolanda Bautista, Fernando Aldaco, Miguel Lazaro, Renata Baez, Raquel Gerson, Carolina Blanco

      • Abstract
      • Presentation
      • Slides

      Background

      Immunotherapy is now the standard of care for non-small cell lung cancer patients without actionable mutations, due to a clear survival benefit in large phase III trials, further this benefit can be translated into the first-line setting, alone or in combination with chemotherapy. Nonetheless, due to several circumstances many patients do not receive immunotherapy as first-line. The effect of the combination therapy with pembrolizumab plus docetaxel in previously-treated NSCLC patients has not been prospectively assessed.

      Method

      In this phase II clinical trial, we evaluated the effect of a combination therapy with pembrolizumab plus Docetaxel (PD) compared with Docetaxel (D) for the treatment of advanced NSCLC patients who had progressed to previous lines of therapy. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety profile.

      Result

      Eighty patients met the inclusion criteria and were enrolled in the study, among which 78 were randomized 1:1. Forty patients were allocated to receive PD, while thirty-eight were allocated to receive D. Baseline characteristics, including sex, age, tobacco index, performance status and EGFR mutation were well-balanced between both arms of the trial. We found a statistically significant difference in terms of ORR (42.5% vs. 15.8%; OR: 3.9 [95%CI: 1.34-11.5]; p=0.01), in patients receiving PD compared with D alone. Further, patients receiving PD had a significantly longer PFS compared with those receiving D monotherapy (9.5 months [95%CI: 4.2-NR] vs. 3.9 [95%CI: 3.2-5.7]; HR: 0.24 [95%CI: 0.13-0.46]; p<0.001). In the multivariate analysis the therapeutic intervention was an independently associated factor with better PFS (Figure). In terms of safety, a total of 22.5% vs. 5.3% of patients experienced any-grade pneumonitis in the PD and D arm of the trial respectively (p=0.048), while 27.5% vs. 16% experienced any-grade hypothyroidism (p=0.20). No new safety signals were identified.

      Conclusion

      Patients who receive the combination therapy have a significantly increased ORR and PFS, with a significant decrease in the hazard of progressing. This work was performed through a grant from MSD (Investigator Initiated Study). The sponsor did not have any role in the acquisition or interpretation of the data.


      pfs_figure 1.png
      Figure. Kaplan-Meier curve for the progression-free survival of patients in the experimental (P+D) vs. the control (D) arm of the trial.

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      MA11.04 - Platinum Doublet + Durvalumab +/- Tremelimumab in Patients with Advanced NSCLC: A CCTG Phase IB Study - IND.226 (Now Available) (ID 927)

      14:00 - 15:30  |  Presenting Author(s): Rosalyn Anne Juergens  |  Author(s): Peter M Ellis, Dongsheng Tu, Desiree Hao, Scott A Laurie, Mihaela Mates, Glenwood D. Goss, John Goffin, Penelope A Bradbury, Mustapha Tehfe, Christian Kollmansberger, Pamela Brown-Walker, Martin Smoragiewicz, Ming Sound Tsao, Lesley Seymour

      • Abstract
      • Presentation
      • Slides

      Background

      Studies of single agent immune checkpoint inhibitors with platinum-based chemotherapy in non-small cell lung cancer (NSCLC) have demonstrated survival benefit over chemotherapy alone. The primary objective of this multi-centre study was to evaluate the safety and tolerability of durvalumab (Du), a PD-L1 inhibitor, +/- tremelimumab (Tr), a CTLA-4 inhibitor, with one of four standard platinum-doublet regimens (pemetrexed (pem), gemcitabine, etoposide (each with cisplatin or carboplatin) or nab-paclitaxel (with carboplatin)), in order to establish a recommended phase II dose (R2PD) for each combination. This abstract updates the results in the NSCLC cohort in this study.

      Method

      Patients (pts), regardless of tumour PD-L1 status, were enrolled into one of six dose levels (Table 1). Dose escalation was according to a Rolling Six type design. Concurrent enrollment of cohorts was allowed. ind 226 abstract wclc methods.png

      Result

      Seventy-three pts (median age=63 (range 34-80); 52% female; 77% non-squamous) were enrolled. The majority of drug-related adverse events (AEs) were grade 1 or 2. Most AEs were related to chemotherapy; other AEs were chemotherapy or immune-related (renal, hepatic, skin and pulmonary toxicity). AEs that were considered related to Du or Tr (immune related AEs (irAEs)) were mainly grade 1 or 2. The most common irAEs were fatigue (64%), rash/itch (42%), diarrhea/colitis (34%), anorexia (22%), thyroid dysfunction (19%), and nausea/vomiting (21/12%). The most common grade 3 or 4 irAEs were diarrhea/colitis (11%), fatigue (10%), and rash (5%). No treatment related grade 5 toxicities were reported. Twenty pts (27%) discontinued treatment due to an AE. Twelve pts (16%) discontinued treatment for toxicity related to D+/-T. Objective response rate (ORR) was 50.7% (95% CI = 38.7-62.6%). Median progression free survival (mPFS) was 6.5 months (95% CI = 5.5-9.4). Median overall survival (mOS) was 19.8 months (95% CI = 14.8-not yet reached). ORR was similar for all levels of PD-L1 staining including PD-L1 negative patients. ORR for pts with EGFR mutations (N=5) was similar to the ORR of wild type pts. Exploratory analyses suggest mPFS and mOS were longer in patients who experienced irAEs.

      Conclusion

      In this PD-L1 unselected patient population, Du and Tr can be safely combined with full doses of platinum-doublet chemotherapy. The ORR, mPFS and mOS are similar to results reported from other immunotherapy + chemotherapy combination trials. A randomized trial, CCTG BR.34, is evaluating the incremental benefit of adding platinum doublet to Du+Tr.

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      MA11.05 - Discussant - MA11.01, MA11.02, MA11.03, MA11.04 (Now Available) (ID 3764)

      14:00 - 15:30  |  Presenting Author(s): Lizza Hendriks

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA11.06 - A PII Study of Toripalimab, a PD-1 mAb, in Combination with Chemotherapy in EGFR+ Advanced NSCLC Patients Failed to Prior EGFR TKI Therapies (Now Available) (ID 1160)

      14:00 - 15:30  |  Presenting Author(s): Jie Zhang  |  Author(s): Caicun Zhou, yanqiu Zhao, Xiaoqian Mu, Jianying Zhou, Zhang Bao, Yun Fan, Yanjun Xu, Yongqian Yong Shu, Renhua Guo, Xiaoqing Liu, Hong Wang, Helong Zhang, Lin Deng, Ningqiang Ma, Jianxing He, Yalei Zhang, mo Chen, Yinrui Jiang

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR TKI is the standard 1st line therapy for the patients (pts) with advanced NSCLC harboring EGFR mutations. While PD-1 checkpoint blockade has become an integral component of disease management for EGFR wild type NSCLC pts at various settings, platinum-based chemotherapy is still the standard of care for EGFR mutated NSCLC pts who progress after EGFR targeting therapy. Early attempts to combine EGFR TKI with checkpoint blockade had resulted in exacerbated immune related toxicity in the lung. Here we aimed to prospectively evaluate toripalimab, a humanized PD-1 mAb approved for 2nd line treatment of melanoma, in combination with chemotherapy to treat EGFR mutated NSCLC pts after failure of EGFR targeting therapy.

      Method

      This is a phase II, multicenter, open-label, single-arm study for pts with EGFR activating mutations who have failed prior EGFR-TKI therapies without T790M mutation or failed osimertinib treatment. Pts were treated with 240mg or 360mg fixed dose toripalimab once every 3 weeks in combination with carboplatin and pemetrexed for up to 6 cycles, followed by toripalimab plus pemetrexed maintenance therapy until disease progression or intolerable toxicity. Primary endpoint was objective response rate (ORR) at week 12 as assessed by investigator per RECIST v1.1 once every 6 weeks. Secondary endpoints were safety, ORR, DOR, DCR, TTR, PFS, OS, PK and immunogenicity.

      Result

      f14_2_1_3_pub.png

      Forty pts were enrolled from Apr 25, 2018 to March 22, 2019 with 52.5% female pts and a median age of 57.5. 57.5% pts harbored EGFR exon19 deletion while 42.5% pts had exon21 L858R mutation. Only 1 pt had T790M mutation who progressed after osimertinib treatment. In ITT population, 13 confirmed partial response (PR) and 22 stable disease (SD) were observed at week 12 for a 32.5% ORR. As of Jul 25 2019, among 40 pts, 20 confirmed PR and 15 SD were observed for a 50% ORR (95% CI, 33.8% to 66.2%) and an 87.5% DCR (95% CI, 73.2% to 95.8%). Median progression free survival (PFS) was 7.0 months, and median duration of response (DOR) was 7.0 months. Treatment emergent adverse events (TEAE) occurred in 39 (97.5%) of the pts, grade 3 or higher events occurred in 25 (62.5%) of pts including two deaths. Most common AE included leukopenia, neutropenia, thrombocytopenia, anemia, nausea, and loss of appetite. Treatment discontinuation due to AE occurred in 4 (10%) of the pts.

      Conclusion

      Anti-PD-1 mAb, toripalimab in combination with carboplatin and pemetrexed has shown a promising anti-tumor efficacy with a tolerable safety profile for advanced NSCLC patients with EGFR mutated who progressed after EGFR TKI therapies. Pts will be continuously monitored for safety and efficacy readouts (DOR, PFS and OS). A phase III registration study will be initiated in May 2019.

      (Clinical trial information: NCT03513666)

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      MA11.07 - Efficacy of Immune-Checkpoint Inhibitors and EGFR-TKIs in NSCLC Patients with High PD-L1 Expression (Now Available) (ID 667)

      14:00 - 15:30  |  Presenting Author(s): Ken Masuda  |  Author(s): Hidehito Horinouchi, Midori Tanaka, Ryoko Higashiyama, Yuki Shinno, Jun Sato, Tatsuya Yoshida, Yuji Matsumoto, Yasushi Goto, Shintaro Kanda, Noboru Yamamoto, Yuichiro Ohe

      • Abstract
      • Presentation
      • Slides

      Background

      Recently, several studies have demonstrated that patients with non-small cell lung carcinoma (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations show poor clinical outcomes in response to treatment with anti-programmed cell death-1 (PD-1) inhibitors. Conversely, EGFR tyrosine kinase inhibitors (EGFR-TKIs) are not effective in NSCLC showing high programmed death ligand 1 (PD-L1) expression levels. In this study, we retrospectively investigated the relationship between high PD-L1 expression and the efficacy of PD-1 inhibitors and EGFR-TKIs in patients with NSCLC.

      Method

      The subjects of this study were patients with NSCLC who had received treatment with PD-1 inhibitors at the National Cancer Center Hospital between March 2017 and December 2018. The PD-L1 expression in the tumor cells was divided into two groups based on the tumor proportion score (TPS): <50% (low) and ≥50% (high).

      Result

      Of the 414 patients treated with PD-1 inhibitors, the 263 patients in whom the PD-L1 expression levels could be evaluated were considered as being eligible for inclusion in this study. Among the 153 patients with high PD-L1 expression, we assessed the efficacy of PD-1 inhibitors according to the EGFR mutation status. The objective response rate (ORR) was 29.4% (95% confidence interval [CI], 1.3 to 53.1) in the EGFR-mutated patients and 43.4% (95% CI, 35.4 to 51.8) in the EGFR wild-type patients. The median progression-free survival (PFS) was 5.3 months (95% CI, 1.3 to 12.4) in the EGFR-mutated patients and 8.3 months (95% CI, 6.0 to 11.7) in the EGFR wild-type patients (hazard Ratio [HR] = 0.62; 95% CI, 0.62 to 1.14). A total of 33 patients received EGFR-TKI therapy. We assessed the efficacy of EGFR-TKIs according to the PD-L1 expression level. The ORR was 50.0% (95% CI, 28.0 to 72.0) in the high PD-L1 expression group and 52.9% (95% CI, 31.0 to 73.8) in the low PD-L1 expression group. The median PFS was 18.8 months (95% CI, 2.8 to 35.7) in the high PD-L1 expression group and 12.7 months (95% CI, 7.2 to 20.9) in the low PD-L1 expression group (HR = 0.83; 95% CI, 0.38 to 1.81).

      PD-L1 High

      EGFR+

      PD-L1 High

      EGFR−

      PD-L1 Low

      EGFR+

      PD-L1 Low

      EGFR−

      Total N

      17

      136

      18

      92

      Median age, years (range)

      62 (47–85)

      62 (33–87)

      64.5 (37–83)

      62 (33–83)

      Sex (n)

      Female

      Male

      7

      10

      36

      100

      15

      3

      25

      67

      ECOG PS (n)

      0, 1

      2

      14

      3

      125

      11

      16

      2

      81

      11

      Smoking history (n)

      Never-smoker

      Smoker

      7

      10

      21

      115

      12

      6

      13

      79

      EGFR mutation status (n)

      Ex 19 del

      L858R

      Others

      7

      6

      4

      13

      2

      3

      ICI agent used (n)

      Pembrolizumab

      Nivolumab

      11

      6

      105

      31

      4

      14

      21

      71

      Line of ICI therapy (n)

      First-line

      Second-line

      Third-line or more

      2

      3

      12

      85

      42

      9

      5

      64

      23

      0

      2

      16

      Efficasy

      ORR (%)

      PD-1 inhibitors

      EGFR-TKIs

      PFS (months)

      PD-1 inhibitors

      EGFR-TKIs

      29.4

      50.0

      5.3

      18.8

      43.4

      8.3

      0

      52.9

      1.6

      12.7

      16.3

      3.8

      Conclusion

      Even in a population of NSCLC patients showing high PD-L1 expression, the efficacy of PD-1 inhibitors tended to be lower in the EGFR-mutated patients as compared to the EGFR wild-type patients. In regard to EGFR-mutated patients with a PD-L1 TPS of ≥50%, our findings suggested that high PD-L1 expression might not predict a poor efficacy of EGFR-TKIs.

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      MA11.08 - Discussant - MA11.06, MA11.07 (Now Available) (ID 3765)

      14:00 - 15:30  |  Presenting Author(s): Qing Zhou

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      • 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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      • Abstract
      • Presentation
      • Slides

      Background

      Neoadjuvant PD-1 blockade has emerged as a promising treatment for resectable NSCLC. The neoadjuvant setting provides a unique opportunity to examine temporal-spatial dynamics of the T cell repertoire in the peripheral and tumoral compartments in response to PD-1 blockade.

      Method

      T-cell receptor (TCR) repertoire dynamics and composition were assessed in matched tumor, normal lung, and longitudinal peripheral blood from 20 NSCLC patients treated with neoadjuvant nivolumab (NCT02259621) and were correlated with major pathologic response (MPR , ≤10% viable tumor in resected specimen) at the time of resection. Treatment-induced dynamics of activated T cell clonotypes were additionally evaluated using TCR sequencing (TCRseq) of flow-sorted PD-1+ T cell populations. To focus on the phenotype of on-treatment intratumoral T cell clones that were recruited from the periphery, combined single-cell RNAseq/TCRseq was performed on post-treatment tumors of 6 patients (3 MPR and 3 non-MPR).

      Result

      MPR was associated with a more clonal intratumoral TCR repertoire and greater clonotypic sharing between pre-treatment blood and post-treatment tumor bed relative to non-MPR. Peripheral repertoire remodeling in response to anti-PD-1 treatment correlated with increased tumor infiltration. Specifically, in patients with MPR, the post-treatment tumor bed was enriched with T cell clones that were peripherally expanded between 2-4 weeks after PD-1 blockade. Clonotypic tracking of the peripherally expanded clones revealed persistence of those clones in the periphery 1+ years following surgical resection and cessation of PD-1 blockade. Single-cell RNAseq/TCRseq analyses revealed distinct phenotypes of peripherally expanded TIL for patients with MPR, with upregulated gene programs associated with cytotoxicity and cytoprotective effects against oxidative stress. Long-term peripherally-persistent TILs had significant upregulation of genes including GZMK, DUSP2, NKG7, 4-1BB and down-regulation of CTLA-4, CXCL13 and PDCD1 as compared to short-lived clones.

      Conclusion

      Our findings support the notion that neoadjuvant checkpoint blockade expands anti-tumor T cell clones in the periphery that can accumulate in tumor bed, facilitate tumor regression, and promote clonotypic persistence in the periphery. Importantly, our data demonstrate the systemic effect of neoadjuvant PD-1 blockade and indicate that the periphery may be an underappreciated originating compartment of effective anti-tumor immunity.

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      MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)

      14:00 - 15:30  |  Presenting Author(s): John Victor Heymach  |  Author(s): Ferdinandos Skoulidis, Kathryn C. Arbour, Matthew Hellmann, Pradnya Dinkar Patil, Melina E Marmarelis, Dwight Hall Owen, Mark Awad, Joseph C. Murray, Benjamin Philip Levy, Jessica Hellyer, Justin F. Gainor, Tyler Stewart, Sarah B. Goldberg, Anastasios Dimou, Christine M Bestvina, Amy Lauren Cummings, Yasir Elamin, Vincent Lam, Jianjun Zhang, Catherine Shu, Jonathan Wesley Riess, Collin M Blakely, Chad V. Pecot, Laura Mezquita, Fabrizio Tabbò, Adrian G Sacher, Matthias Scheffler, Biagio Ricciuti, Deepti Venkatraman, Hira Rizvi, Corinne Liu, Rocio Perez Johnston, Ying Ni, Joseph Azok, Melanie Wain Kier, Sharyn I Katz, Kurtis D. Davies, Jeremy P Segal, Lauren Ritterhouse, Hiram Shaish, LUDOVIC Lacroix, Regan Memmott, John R Madrigal, Jonathan Goldman, Sally CM Lau, Jonathan Killam, Zenta Walther, Brett Carter, Mark Woodcock, Jack Roth, Stephen Swisher, Natasha B Leighl, Subba Digumarthy, Meghan Mooradian, Julia Rotow, Juergen Wolf, Giorgio Vittorio Scagliotti, David Planchard, Benjamin Besse, Trever G Bivona, David R Gandara, Edward Garon, Naiyer A Rizvi, D. Ross Camidge, Kurt A Schalper, Roy S. Herbst, Alice T. Shaw, Joel W Neal, Heather A Wakelee, Julie R Brahmer, Pasi A Jänne, David P Carbone, Charu Aggarwal, Nathan Pennell, Charles M Rudin, Vassiliki A Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Background

      Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.

      Method

      620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.

      Result

      Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.

      Conclusion

      In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.

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      MA11.12 - Discussant - MA11.09, MA11.10, MA11.11 (Now Available) (ID 3766)

      14:00 - 15:30  |  Presenting Author(s): Ana Zimmer Gelatti Gelatti

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    ES25 - Liquid Biopsy (ID 27)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      ES25.02 - Liquid Biopsy: Utility for Surveillance in Early Stage (Now Available) (ID 3288)

      14:30 - 16:00  |  Presenting Author(s): Lecia Sequist

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA04 - Immuno Combinations and the Role of TMB (ID 126)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      OA04.05 - KEYNOTE-021: TMB and Outcomes for Carboplatin and Pemetrexed With or Without Pembrolizumab for Nonsquamous NSCLC (Now Available) (ID 2630)

      15:15 - 16:45  |  Author(s): Lecia Sequist

      • Abstract
      • Presentation
      • Slides

      Background

      KEYNOTE-021 cohort C was the first study to show antitumor activity for pembrolizumab plus platinum-based chemotherapy in previously untreated advanced nonsquamous NSCLC; the combination significantly improved efficacy vs platinum-based chemotherapy alone in cohort G. We explored the relationship between TMB and outcomes in KEYNOTE-021 cohorts C and G.

      Method

      All patients in cohort C received pembrolizumab plus carboplatin and pemetrexed. Patients in cohort G were randomized 1:1 to pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone. TMB was determined by whole-exome sequencing of tumor and matched normal DNA. Association of TMB (continuous, log10 transformed) with outcomes for pembrolizumab plus chemotherapy and chemotherapy alone were assessed using logistic regression for ORR and Cox proportional hazards models for PFS and OS adjusted for ECOG PS; statistical significance was determined at the 0.05 level without multiplicity adjustment. The correlation of TMB (continuous, log10­ transformed) with PD-L1 TPS (square root scale) was assessed in the combined population. The clinical utility of TMB for ORR using a prespecified TMB cutpoint of 175 Mut/exome (~13 Mut/Mb by FoundationOne CDx) was assessed for pembrolizumab + chemotherapy.

      Result

      TMB data were evaluable for 70 patients: 12/24 (50.0%) in cohort C, 32/60 (53.3%) in the cohort G pembrolizumab plus chemotherapy arm, and 26/63 (41.3%) in the cohort G chemotherapy only arm; median age was 65 years (IQR, 57-70) and 61% were female. Baseline characteristics were generally similar in the TMB-evaluable and total populations. TMB as a continuous variable was not significantly associated with ORR, PFS, or OS for pembrolizumab plus chemotherapy (one-sided P = 0.180, 0.187 and 0.081, respectively) or chemotherapy alone (one-sided P = 0.861, 0.795 and 0.763, respectively). There was no significant correlation between TMB and TPS (r=0.12, P=0.34). ORR (95% CI) in patients treated with pembrolizumab plus chemotherapy was 60.8% (38.5-80.3) in the 23 patients with TMB <175 and 71.4% (47.8-88.7) in the 21 patients with TMB ≥175.

      Conclusion

      In this exploratory analysis, TMB was not significantly associated with efficacy of pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone as first-line therapy for metastatic nonsquamous NSCLC. TMB was not significantly correlated with PD-L1 expression. Among pembrolizumab plus chemotherapy-treated patients, ORR was high in both the TMB low and high subgroups. Sample size is a limitation of this study; exploration in larger datasets is required to understand any differential efficacy of pembrolizumab plus chemotherapy vs chemotherapy alone based on TMB status.

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    WS06 - Women in Thoracic Oncology Networking Event (ID 355)

    • Event: WCLC 2019
    • Type: Workshop
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 1
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      WS06.12 - Networking Table 10: Social Activism in Medicine (ID 4080)

      07:00 - 08:00  |  Presenting Author(s): Lecia Sequist

      • Abstract

      Abstract not provided