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S.I. Rothschild



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    ISS03 - Industry Supported Symposium: Non-Small Cell Lung Cancer: The Programmed Death-Ligand 1 (PD-L1) Receptor as a Target for Monotherapy and in Combination – Merck-Pfizer Alliance (ID 437)

    • Event: WCLC 2016
    • Type: Industry Supported Symposium
    • Track:
    • Presentations: 1
    • Moderators:S. Popat
    • Coordinates: 12/04/2016, 03:30 PM - 05:00 PM, Hall C2
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      ISS03.04 - Anti-PD-L1 Combined with Other Agents in NSCLC: Immuno-Oncology Combinations (ID 7040)

      S.I. Rothschild

      • Abstract

      Abstract not provided

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    MA16 - Novel Strategies in Targeted Therapy (ID 407)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
    • Now Available
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      MA16.03 - Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers (Now Available) (ID 4325)

      S.I. Rothschild

      • Abstract
      • Presentation
      • Slides

      Background:
      GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.

      Methods:
      A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).

      Results:
      165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.

      Conclusion:
      RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.

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    P1.07 - Poster Session with Presenters Present (ID 459)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
    • Now Available
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      P1.07-041 - Validation of Prognostic Scores in Small Cell Lung Cancer (Now Available) (ID 6205)

      S.I. Rothschild

      • Abstract
      • Slides

      Background:
      Treatment decisions in small-cell lung cancer (SCLC) are made based on the extent of the disease. However, the outcome differs among patients at the same stage. A simple tool to predict outcome in SCLC patients would be helpful for decision-making. In recent years, several prognostic scores have been proposed. However, most of them have never been validated in independent patient population.

      Methods:
      From January 2000 to December 2010, 92 SCLC patients were treated at our institution. Data acquisition from consecutive patients was done through patients’ medical records, and blood results recorded at the time of diagnosis. Univariate and multiple cox regression analyses of survival were performed to assess the prognostic value of relevant clinical and laboratory factors for SCLC. Furthermore, we investigated the relationship between seven published prognostic scores for SCLC and overall survival (OS).

      Results:
      We recently published clinical data of our study population (Hagmann R. J Cancer 2015). In a univariate analysis, we evaluated 29 parameters. Staging (p<0.001), number of metastastic sites (p<0.001), liver metastasis (p<0.001), bone metastasis (p<0.001), adrenal gland metastasis (p=0.028) and response to initial therapy (p<0.001) were significantly related to OS. From the established laboratory markers hypoalbuminemia (<35 g/l; p=0.044), hyponatraemia (<131 mmol/l; p=0.041), and elevated alkaline phosphatase (AP) (≥ 129 U/l; p<0.001) significantly predicted OS. Multivariate analysis confirmed staging (HR 2.7; p=0.022) and elevated AP (HR 3.3; p=0.004) as independent prognostic factors. The Manchester Score incorporating LDH, tumor stage, serum sodium, Karnofsky performance status, AP and serum bicarbonate (Cerny T. Int J Cancer 1987) was the only published scoring system significantly associated with OS. Patients in good, intermediate and poor prognosis groups had a median OS of 12.9, 6.6 and 5.8 months, respectively (p=0.008).

      Conclusion:
      We confirmed the prognostic role of the Manchester Score in an independent patient population whereas the reliability of more complex and recent scoring systems could not be validated. We therefore recommend using simple clinical and laboratory factors instead of complex scores to estimate prognosis of SCLC patients.

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    P1.08 - Poster Session with Presenters Present (ID 460)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Surgery
    • Presentations: 1
    • Now Available
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      P1.08-065 - Resection of Isolated Brain Metastasis Improves Outcome of Non Small-Cell Lung Cancer (NSCLC) Patients: A Retrospective Multicenter Study (Now Available) (ID 6132)

      S.I. Rothschild

      • Abstract
      • Slides

      Background:
      Metastatic non-small cell lung cancer (NSCLC) is an incurable disease. Selected patients with solitary brain metastasis from NSCLC can achieve long-term survival following metastasectomy. We analyzed the outcome of all consecutive and unselected patients undergoing resection of brain metastases in two cancer centers in Switzerland to assess safety and efficacy of brain metastasis resection in NSCLC.

      Methods:
      119 consecutive NSCLC patients undergoing surgical resection of brain metastases from two centers in Switzerland (University Hospital Basel, Cantonal Hospital St. Gallen) between 2000 and 2014 were analyzed. Measured outcomes were extent of resection, resection status, postoperative complications and overall survival (OS). We used the log-rank test to compare unadjusted survival probabilities and multivariable Cox regression to investigate potential prognostic factors with respect to OS.

      Results:
      Median age was 60.5 years, 56% were male, 74% were smokers, 55% had adenocarcinoma. Median OS of the whole cohort was 18.0 months. 1-year survival rate was 63%, 12% of patients were alive after 5 years. In total, 146 brain metastases were resected; the maximum number of resected metastases was 4 (median: 1). Median diameter of resected metastases was 25 millimeters (range, 6-70 mm). About half of metastases were localized in the frontal cortex or the cerebellum. 86% of patients received postoperative radiotherapy. 63% of patients were treated with whole brain radiation, 12.6% received stereotactic radiotherapy. Median dose of postoperative radiotherapy was 30 Gy. Patients not receiving adjuvant radiotherapy (n=11) had a significantly worse outcome (median OS 9.0 vs. 20.2 months, p=0.002). Patients with more than one brain metastasis (n=21) had a significantly worse outcome compared to those with a solitary metastasis (median OS 13.5 vs. 19.5 months, p=0.006). Also patients with extracerebral metastases (n=33) had a significantly poorer outcome (median OS 14.0 vs. 23.1 months, p=0.005). Patients with non-squamous histology (n=98) had a better outcome than patients with squamous cell carcinoma (median OS 22.6 vs. 12.0 months, p=0.019). 21% of patients experienced postoperative complications, including need for surgical reintervention (5.8%), neurological deficits (4.2%), infection (4.2%), stroke (3.4%) and others (11.8%). The occurrence of postoperative complications was not associated with outcome. In the multivariate analysis existence of extracerebral metastases and resection of more than one brain metastasis were independent negative prognostic factors.

      Conclusion:
      Patients with isolated brain metastasis from NSCLC in the absence of extracranial metastasis should be evaluated for metastasectomy. Prospective trials are needed to characterize the patient population experiencing the greatest benefit from a surgical procedure.

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    P2.03a - Poster Session with Presenters Present (ID 464)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      P2.03a-004 - Second-line Therapy Improves Overall Survival in Primary Refractory Non Small-Cell Lung Cancer (NSCLC) Patients (Now Available) (ID 6114)

      S.I. Rothschild

      • Abstract
      • Slides

      Background:
      The effect of palliative chemotherapy for non-small cell lung cancer (NSCLC) is well established. However, little is known on the efficacy of cytotoxic chemotherapy in patients whose tumors are refractory to first-line chemotherapy. We analyzed the outcome of all consecutive and unselected patients receiving palliative chemotherapy in a single institution to assess the efficacy of second-line chemotherapy in primary refractory NSCLC.

      Methods:
      462 consecutive patients with palliative treatment for NSCLC at the University Hospital Basel between 1990 and 2009 were analyzed. Measured outcomes were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Patients with progressive disease (PD) as best response to first-line treatment were compared to patients with stable disease (SD), partial (PR) or complete remission (CR). Chi-square test was used for discrete, and Mann Whitney U tests for continuous variables, respectively. Probabilities of survival were calculated using the Kaplan-Meier estimator. The log-rank test was used for comparing groups.

      Results:
      Median age was 63 years, 71% were male, 81% were smokers and 53% had adenocarcinoma. Median OS of the whole cohort was 11.3 months. 62.3% of patients were treated with a platinum-based (48.3% cisplatin-based) first-line therapy. Median PFS for first-line therapy was 3.0 months. 192 patients (41.6%) were primary refractory on first-line therapy. Median OS was significantly shorter for refractory patients compared to patients with CR, PR or SD (9.2 vs. 14.5 months, p<0.0001). Poorer initial performance status was significantly associated with primary refractory disease (p=0.015). All other baseline characteristics did not differ between refractory and responding patients. 67 (35%) primary refractory patients received a second-line therapy. The clinical benefit rate (CR+PR+SD) from second-line therapy was lower in primary refractory patients (33.9% vs. 43.5%, p=0.023). Median PFS for second-line therapy was shorter for primary refractory patients (2.2 vs. 4.6 months, p=0.26). Median OS was significantly longer for refractory patients receiving second-line chemotherapy vs. best supportive care (13.6 vs. 5.5 months, p<0.0001).

      Conclusion:
      More than 40% of patients are primary refractory to palliative first-line therapy. These patients have a poor prognosis. However, active second-line chemotherapy can significantly improve the outcome compared to best supportive care. Median OS for patients receiving second-line chemotherapy was close to patients with initial response or stable disease. Patients with primary refractory NSCLC should be offered further active therapy. These real life data for primary refractory patients form the basis against which immunotherapies, the current standard second line treatment, can be compared.

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    P3.06 - Poster Session with Presenters Present (ID 492)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Trial Design/Statistics
    • Presentations: 1
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      P3.06-010 - Clinical Outcomes of Non-Small Cell Lung Cancer (NSCLC) Patients with ALK Co-Mutations (EGFR or KRAS) Receiving Tyrosine Kinase Inhibitors (TKI) (ID 4729)

      S.I. Rothschild

      • Abstract

      Background:
      Anaplastic lymphoma kinase (ALK) rearrangements with concurrent epidermal growth factor (EGFR) or Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations occur very rarely. Outcomes with TKI in these patients (pts) are poorly understood.

      Methods:
      Outcomes of pts with metastatic NSCLC and double mutations of ALK/EGFR or ALK/KRAS detected by FISH (ALK) and PCR or NGS (EGFR/KRAS) from six oncology centres in Switzerland were retrospectively analysed.

      Results:
      A total of 15 pts with adenocarcinoma were identified, 53% were females and tumor stages were IIIB (6%), IVA (27%) and IVB (67%). Six pts had a co-mutation of ALK/EGFR and nine ALK/KRAS. ALK/EGFR pts were younger (54 vs. 64 years) and less likely to be (ex-) smokers (34% vs. 77%). In total, 12 pts received an ALK-TKI (11x crizotinib, 1x alectinib, 2x ceritinib, 1x lorlatinib). EGFR-TKIs were given to five EGFR/ALK pts (4x afatinib, 2x osimertinib, 3x erlotinib). 33% received > 1 ALK-or EGFR-TKI. TKI were given as first-line (1L) in 40% (4x ALK/KRAS, 2x ALK/EGFR). Pts with ALK/KRAS co-mutation: Seven of eight pts (88%) were primary refractory to ALK-TKI treatment (all crizotinib). One patient has ongoing disease stabilization since 26 months. Three of six pts responded to 1L platinum-based chemotherapy with a median progression free survival (PFS) of 4.25 months (range: 1 month - NR). Pts with ALK/EGFR co-mutation: Two of four pts responded to ALK-TKI: one PR to crizotinib+erlotinib combination, one PR to alectinib and lorlatinib. Median PFS on first ALK-TKI was 3.75 months (range: 1-7months). Three of five pts (60%) achieved one or more responses to EGFR-TKI in different lines of therapy (4x PR: 3x afatinib, 1x osimertinib, CR: 1x osimertinib). Median PFS on first EGFR-TKI was 4.5 months (range: 3-7 months). Two of five pts responded to platinum-based chemotherapy (median PFS: 5.5 months (range: 0.25-10 months)).

      Conclusion:
      De novo concurrent ALK/KRAS alterations are associated with resistance to ALK-TKI treatment in seven out of eight pts, although one patient achieved ongoing disease stabilization for 26 months. Thus, platinum-based chemotherapy should be 1L treatment for these patients. In ALK/EGFR pts outcomes with ALK and EGFR-TKI seem inferior to what would be expected in pts with either alteration. EGFR-TKIs may potentially be more active compared to ALK-TKIs in ALK/EGFR pts. Worse outcomes to ALK-TKI may partly be related to false-positive ALK test results. Further studies are needed to clarify which patients may still benefit from the respective TKI.