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M. Majem



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    OA03 - Immunotherapy Checkpoint Inhibitors in Advanced NSCLC (ID 367)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      OA03.07 - KEYNOTE-010: Durable Clinical Benefit in Patients with Previously Treated, PD-L1-Expressing NSCLC Who Completed Pembrolizumab  (ID 6769)

      11:00 - 12:30  |  Author(s): M. Majem

      • Abstract
      • Presentation
      • Slides

      Background:
      Checkpoint inhibitors such as the anti–PD-1 monoclonal antibody pembrolizumab have demonstrated antitumor activity and a manageable safety profile in several advanced malignancies. Although checkpoint inhibitors are rapidly becoming a standard-of-care therapy in multiple tumor types, the optimal treatment duration has not been established. We assessed outcomes in patients who completed the maximum 24 months of pembrolizumab in the phase 3 KEYNOTE-010 study (NCT01905657), in which pembrolizumab provided superior OS over docetaxel in patients with previously treated, PD-L1–expressing advanced NSCLC.

      Methods:
      1034 patients with advanced NSCLC that progressed after ≥2 cycles of platinum-based chemotherapy (and an appropriate therapy for targetable EGFR and ALK aberrations if present) and had a PD-L1 tumor proportion score ≥1% were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg Q3W or to docetaxel 75 mg/m[2] until disease progression, intolerable toxicity, or physician or patient decision; the maximum duration of pembrolizumab was 24 months of uninterrupted treatment or 35 cycles, whichever was later. Response was assessed per RECIST v1.1 by independent central review every 9 weeks. After completion of 24 months/35 cycles, patients continued to undergo imaging every 9 weeks; patients with subsequent disease progression were eligible for a second treatment course if they did not receive other anticancer therapy after stopping pembrolizumab.

      Results:
      In the overall population, median OS was longer (10.5 months for pembrolizumab Q2W, 13.4 months for pembrolizumab Q3W, and 8.6 months for docetaxel) and 24-month OS rates were higher (30.1%, 37.5%, and 14.5%, respectively) with pembrolizumab compared with docetaxel. Of the 691 patients allocated to pembrolizumab, 47 patients received 35 cycles of pembrolizumab and were included in this analysis. As of the September 30, 2016 data cutoff date, all patients had completed all 35 cycles of treatment, but one withdrew from the study treatment after completing 35 cycles. Best overall response (ORR) among these 47 patients was complete response (CR) in 3 (6%) patients and partial response (PR) in 39 (83%) patients, for an ORR of 89%; 5 (11%) patients experienced stable disease (SD). Two of these patients experienced disease progression since stopping pembrolizumab and two of these patients resumed pembrolizumab therapy. As of the cutoff date, none of the 47 patients had died.

      Conclusion:
      With long-term follow-up, the OS benefit has been maintained and pembrolizumab continues to demonstrate superiority over docetaxel. Pembrolizumab provides durable clinical benefit with few patients progressing after completing two years of therapy.

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    P1.02 - Poster Session with Presenters Present (ID 454)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-067 - Repeated Biopsy for Immunohistochemical and Mutational Analysis of Non Small Cell Lung Cancer: Feasibility and Safety (ID 4442)

      14:30 - 15:45  |  Author(s): M. Majem

      • Abstract

      Background:
      Repeated biopsy in lung cancer may be necessary at diagnosis or after cancer progression on initial therapy to properly target treatments. The objective of this study is to evaluate the feasibility and safety of repeated biopsy for immunohistochemical and/or mutational analysis in patients with non small cell lung cancer.

      Methods:
      We have retrospectively analyzed repeated biopsies performed in patients with advanced non small cell lung cancer during the last 4 years. The technical success rates for the repeated biopsy and the adequacy rates of specimens were evaluated. Biopsy-related complications were recorded. Clinical details were collected, specially focusing in EGFR mutation data.

      Results:
      110 repeated biopsies were performed in 74 patients (34 women, 40 men, mean age 63 [36-84]), the histology was: 74% adenocarcinoma, 12% squamous cell carcinoma, 11% NOS, 3% other. The mean number of repeated biopsies per patient was 1 (1-4). The main reasons for repeated biopsy were immunohistochemical +/- mutational analysis (34/110, 31%), mutational analysis (16/110, 14.6%) and EGFR at progression (28/110, 24.4%). The technical success rate for biopsy was 98/110 (89.1%), and postprocedural complications occurred in 3/110 cases: 2 pneumothorax and 1 wound infection. Biopsy specimens came mostly from primary tumor (56/110, 51%), lymph nodes (26/110, 23.6%) and pleura (9/110, 8.2%), the most used technique was bronchoscopy +/- EBUS (45/110, 40%), followed by percutaneous transthoracic lung biopsy (28/110, 26%) and thoracoscopy and/or mediastinoscopy: (19/110, 17%). Results from repeated biopsy were used to select the next line of treatment in 86/110 procedures (78%), and 40/86 of them (46.5%) allowed to include the patient in a clinical trial. 28 repeated biopsies were performed in 21 EGFR mutant lung cancer patients with acquired resistance at disease progression, T790M was detected in 13/28 (46%) of samples, corresponding to 10/21 (47.6%) EGFR mutant lung cancer patients.

      Conclusion:
      Our data demonstrate that repeated biopsy in non small cell lung cancer is safe and clinically feasible. Findings from repeated biopsy were used to direct subsequent treatment in 78% of patients.

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    P2.04 - Poster Session with Presenters Present (ID 466)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      P2.04-013 - Prognosis Factors and Survival Analysis in Thymic Epithelial Tumors (ID 5919)

      14:30 - 15:45  |  Author(s): M. Majem

      • Abstract

      Background:
      Thymic epithelial tumors (TET) include thymomas (T) and thymic carcinomas (TC). TET are rare malignant tumors usually associated with paraneoplastic syndromes (PNPS). The objective of the study is to describe our experience and to analyze the prognostic factors.

      Methods:
      Retrospective analysis of the clinical and pathological characteristics of 42 patients (pts) diagnosed with TET in our institution from 1990 to 2016. We analysed the outcomes in terms of progression-free survival (PFS) and overall survival (OS) and their association with clinical factors: age, perfomance status, presence of PNPS, TNM staging, WHO classification, complete resection and treatment. Kaplan Meier method and Cox regresion were used.

      Results:
      Mean age:55 years (27-86). 19 (45.2%) : women. First treatment: surgery in 34 pts (81%) and platinum based chemotherapy in 6 pts (14%). 2 pts (5%) were untreated. 14 pts (41%) received postoperative radiotherapy. WHO classification: 6 pts (14.3%) type A, 12 (28.6%) AB, 3 (7.1%) B1, 7 (16.7%) B2, 7 (16.7%) B3 and 7 (16.7%) C. TNM staging: 20 pts (48.8%) stage I,4 (9.8%) stage II, 6 (14.6%) stage III and 9 (22%) stage IV. 25 ptss (59.5%) had PNPS at diagnosis: 21 (50%) myasthenia gravis, 2 (4.75%) aplastic anemia and 2 (4.75%) others. Table 1 shows OS and PFS according to WHO classification:

      WHO C WHO: A, AB, B1, B2, B3 p value HR (univariate) p value
      PFS (months)(95%CI) 21.2 (5.8-36.7) 89.3(69.1-109.6) 0.03 3.12 0.04
      OS (monthS)(95%CI) 66.5 (0-157.5) 296 (98.6-493.3) <0.001 20.2 0.007
      The presence of PNPS were associated with better OS than those without PNPS (236m , 95%CI 147-448m vs 66.5m, 95% CI 1.3-131.7m, p=0.006, HR 0.76, p=0.026 ) and also with early diagnosis (stage I for pts with PNPS 56% vs 42% without PNPS ). In the multivariate analisys, only C type remained stadistically significant (HR:13.5, p=0.024). No diferences were found when using TNM classification or complete resection.

      Conclusion:
      Patients with C type TET had worst prognosis. The presence of a PNPS is associated with better OS possibly due to and early diagnosis.

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    P2.06 - Poster Session with Presenters Present (ID 467)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
    • Presentations: 1
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      P2.06-010 - AZD9291 as 1st-Line Therapy for EGFR Mutant NSCLC Patients with Concomitant Pretreatment EGFR T790M Mutation. The AZENT Study (ID 4267)

      14:30 - 15:45  |  Author(s): M. Majem

      • Abstract

      Background:
      Osimertinib (AZD9291) is a selective and irreversible pyrimidine-based inhibitor of the primary activating and the secondary EGFR mutation, T790M, which is the most common mechanism of acquired resistance to 1st and 2nd-generation EGFR tyrosine-kinase inhibitors (TKIs). Progression-free survival (PFS) with osimertinib was 9.6 and 2.8 months (m) for EGFR mutated (EGFR+) NSCLC patients progressing to prior EGFR TKI therapy with and without EGFR T790M mutation, respectively, indicating that the T790M is a predictive biomarker for osimertinib efficacy. Sixty patients from two expansion cohorts of the same study, received 1st-line osimertinib and obtained a PFS of 19.3m. T790M, arising in cis with the primary activating mutation, confers resistance to EGFR TKIs, even in the absence of drug selection. The coexistence of the pretreatment T790M mutation has been under appreciated, in spite of accumulative evidence that is present in a frequency of 35-60% using different detection methods. In our experience, pretreatment T790M mutation is frequently detected by three specific aspects of the method: tumor microdissection, examination of two separate tumor areas, and the use of a peptic nucleid acid clamp that inhibits wild-type allele amplification. Thus, we designed the first phase IIa study to evaluate the safety and efficacy of osimertinib as 1st-line therapy for patients with metastatic EGFR+ NSCLC and concomitant pretreatment T790M mutation.

      Methods:
      This is a multicenter, single-arm, open-label, non-controlled phase IIa clinical study in Spain. Eligible patients are aged ≥18 years with metastatic EGFR+ NSCLC and by central testing documented presence of pretreatment T790M mutation. Seventy-three patients will receive continuous treatment with osimertinib 80 mg daily until disease progression, intolerable adverse events, consent withdrawal or noncompliance with the study protocol. The primary endpoint is the objective response rate (ORR) assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The trial is designed to detect a ≥70% ORR in this patient population. Secondary objectives include PFS, overall survival, time to treatment failure, duration of response and disease control rate. Additional pre-specified secondary objectives of the study are the longitudinal analysis of EGFR mutations (including the T790M and the C797S mutations) in plasma and serum and the expression analysis of a panel of biomarkers with possible predictive value for osimertinib treatment.

      Results:
      Not applicable

      Conclusion:
      Not applicable

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    P3.02c - Poster Session with Presenters Present (ID 472)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02c-080 - The Beneficial Effect of Platelet Binding to Monocytes on the Clinical Response to Checkpoint Inhibitors (ID 6032)

      14:30 - 15:45  |  Author(s): M. Majem

      • Abstract

      Background:
      Nivolumab is an immune checkpoint inhibitor that reactivates cytotoxic T cells against tumor cells in non-small cell lung cancer (NSCLC) patients (pts). There are many ongoing efforts to find predictive biomarkers for immune checkpoint inhibitors. We have previously reported that platelet can selectively bind to leukocytes and, as a consequence, modify their function. To evaluate whether this modification is relevant for the response to checkpoint inhibitors, we determined the percentage of different subsets of leukocytes with bound platelets in the peripheral blood of pts before starting treatment with Nivolumab.

      Methods:
      Peripheral blood samples were collected at baseline from patients with NSCLC candidates for receiving Nivolumab. After labeling cells with antibodies specific for lymphocytes, monocytes and neutrophils, we added anti-CD41a mAbs (specific for platelets). We next determined the percentage of PDL1+ cells and CD41+ cells in each leukocyte subset by flow cytometry. These results were compared in patients with different clinical response by one-way ANOVA. The clinical response was determined by RECIST v1.1 criteria.

      Results:
      From January 2015 to February 2016, we collected peripheral blood from 12 pts (4 females and 8 males). Mean age at time to starting Nivolumab was 73 (range 53-86). 4 pts were smokers and 8 former smokers. 5 pts were had squamous cell carcinoma and 6 non-squamous cell carcinoma. 6 Pts received Nivolumab in second line and 6 patients in third line. Response after 3 months with Nivolumab: 4 patients with partial or complete response, 4 patients with stable disease and 4 with progressive disease. There were no differences in the baseline percentages of CD4+, CD8+, Natural Killer cells, B lymphocytes, monocytes and neutrophils among the three groups of response. By contrary, the proportion of monocytes with bound platelets (CD14+CD41+/ total monocytes) was significantly higher in patients with response to nivolumab than those with stable or progressive disease (90.28+7.63%, 33.92+7.02 and 61.44+19.5% respectively, p=0.002). And Also, the PDL1 expression on monocytes was different between the three groups (1.9+0.16, 4.37+1.05 and 2.39+0.73 respectively, p=0.003).

      Conclusion:
      The functional modification induced by the platelet binding to the monocytes seems to be beneficial for the clinical response to checkpoint inhibitors.