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S.L. Kass



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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.11 - A Phase II Trial of Paclitaxel, Pemetrexed and Bevacizumab in Patients with Untreated, Advanced Lung Cancers (ID 3142)

      16:15 - 17:45  |  Author(s): S.L. Kass

      • Abstract
      • Presentation
      • Slides

      Background
      Standard front-line treatment for patients with unresectable or metastatic non-small cell lung cancer (NSCLC) is a platinum-based doublet with bevacizumab regimen, which achieves objective response rates (ORR) of 35% and median survival of 12 months. However, many patients with lung cancer are not eligible for cisplatin because of baseline neuropathy, hearing loss, renal insufficiency, or comorbid medical conditions. Although carboplatin is often substituted for cisplatin, it also is associated with similar toxicities, albeit with a smaller risk. This phase II trial of paclitaxel, pemetrexed, and bevacizumab was designed to avert the toxicities of platinum-based chemotherapeutic regimens and determine the efficacy of such a "non-platinum" containing doublet with bevacizumab.

      Methods
      Patients with untreated, advanced NSCLCs were enrolled if they had measurable disease (RECIST 1.0) and adequate organ and marrow function. Patients were excluded if they had squamous cell carcinoma; hemoptysis; symptomatic or hemorrhagic brain metastases; history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess; and myocardial infarction or stroke within 6 months prior to enrollment. For six 28-day cycles, patients received: paclitaxel 90 mg/m[2] (days 1, 8, and 15), pemetrexed 500 mg/m[2] (days 1 and 15), and bevacizumab 10 mg/kg (days 1 and 15). Patients with response or stable disease continued pemetrexed and bevacizumab every 14 days until progression or unacceptable toxicity. Patients were evaluated on days 1, 8 and 15 of each 28-day cycle. To assess response, CT scans were performed after cycles 1 and 2, and every 2 cycles thereafter. ORR was the primary endpoint.

      Results
      Forty-four patients were enrolled: 50% women, median age of 59 years (range, 31 to 77), 89% with Karnofsky performance status ≥80%. Mutation status was known in 38 patients (KRAS, n=16; ALK, n=3; BRAF V600E, n =2; Her2 insertion/PIK3CA, n=1; EGFR Exon 20 insertion, n=1; none, n=15). The ORR was 52% (95% CI, 37-68), with 23 partial responses and no complete responses. The median overall survival and progression-free survival were 17 months (95% CI, 12-33) and 8 months (95% CI, 6-12), respectively. Grade 3/4 toxicities included fatigue (33%); elevated liver function tests (15%); leukopenia (9%); hoarseness (7%); nausea (7%); and anemia (7%). Two patients died on study of respiratory failure, possibly related to therapy. No bleeding events were noted.

      Conclusion
      The “non-platinum” containing regimen of paclitaxel, pemetrexed and bevacizumab is an effective first-line treatment for patients with advanced NSCLCs, regardless of mutational status. Long survival was observed, with acceptable toxicities. This regimen warrants further study.

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-059 - Comparison of the characteristics and clinical course of patients with metastatic KRAS mutant lung cancers (ID 3484)

      09:30 - 16:30  |  Author(s): S.L. Kass

      • Abstract

      Background
      Patients (pts) with KRAS mutant lung cancers have a shorter survival compared to pts withKRAS/EGFR wild type tumors(Johnson et al, Cancer 2013). Whether outcomes for patients with KRASmutant metastatic lung cancers differ by smoking status or specific amino acid substitution is unknown. In order to understand the impact of KRAS mutation subtype in the metastatic setting, we analyzed a large cohort of patients with KRAS mutant metastatic lung cancer.

      Methods
      We identified all pts with KRAS mutant metastatic or recurrent lung cancers from Feb 2005 to Aug 2011. KRAS mutation type, clinical characteristics, and outcomes from diagnosis were obtained from the medical record. A multivariate cox proportion hazard model was used to identify factors associated with overall survival.

      Results
      KRAS mutations were identified in 677 pts (53 at codon 13, 624 at codon 12). Median age: 66 (range 31-89), women: 62%, never smokers: 7%. Pts with transition mutations (n=157) were more likely to be never-smokers (p<0.0001). There was no difference in outcome for pts with KRAS transition versus transversion mutations (p=1) or when comparing current/former smokers to never smokers (p=0.33). There was no difference in overall survival (OS) when comparing specific amino acid substitutions (G12C=366, G12V=141, G12D=114, G12A=68, G13C=27, G13D=23, G12S=19, G12F=11)(p=0.20). Pts with KRAS codon 13 mutant tumors had inferior OS compared to pts with codon 12 mutant tumors, median 13 months (mo) (95% CI 13-17 mo) and 16 mo (95% CI 9-16 mo), respectively (p=0.009). There was no difference in frequency of receiving platinum-based chemotherapy or chemotherapy of any kind between pts with codon 12 and 13 mutant tumors. In a multivariate Cox model which included age, gender and smoking status, KRAS codon 13 mutation was associated with worse overall survival than KRAS codon 12 mutation (HR 1.52 95% CI 1.11-2.08 p=0.008).

      Conclusion
      Among pts with KRAS mutant metastatic lung cancers, smoking history, and specific amino acid substitution do not affect outcome. Among patients with KRAS mutant metastatic lung cancers, those with codon 13 mutations have shorter survival compared to pts with KRAS codon 12 mutations.

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    P1.14 - Poster Session 1 - Mesothelioma (ID 194)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P1.14-002 - Lack of response to chemotherapy for previously treated malignant pleural mesothelioma (MPM) (ID 656)

      09:30 - 16:30  |  Author(s): S.L. Kass

      • Abstract

      Background
      After initial therapy with pemetrexed/platinum, second-line therapy options are not well established. Gemcitabine and vinorelbine are often used based on small trials and first-line data. To augment the existing data, we examined our institutional experience using vinorelbine and gemcitabine in patients with previously treated MPM.

      Methods
      We reviewed the records of all patients treated with vinorelbine and/or gemcitabine as second- or third-line therapy for MPM between 2003 and 2010. Vinorelbine was administered at a dose of 25 mg/m[2] days 1 and 8 in a 3-week cycle and gemcitabine was given at 1000 mg/m[2] days 1, 8, and 15 in 28 day cycles. CT scans were generally performed after every two cycles. Imaging studies were reviewed with a radiologist according to the modified RECIST criteria.

      Results
      60 patients were identified: 33 treated with vinorelbine, 15 with gemcitabine, and 12 with both. Patient characteristics are as follows: 78% men: median age 67 (range 41-85); 63% epithelioid, 19% mixed histology, and 18% sarcomatoid; 83% received first-line pemetrexed-platinum therapy and 10% gemcitabine-platinum therapy. One partial radiographic response was identified among the 56 patients with follow up imaging available for review (Figure 1) giving a response rate of 2% (95% CI 0-5%). With gemcitabine, 10 patients (37%) had radiographic progression, 6 (22%) had clinical progression, 6 (22%) had radiographic stable disease, 4 (15%) had clinically stable disease, and 1 (4%) had radiographic partial response. With vinorelbine, 20 patients (43%) had radiographic progression, 2 (4%) had clinical progression, 19 (42%) had radiographic stable disease, 4 (8%) had clinically stable disease, and there were no responses. 53% experienced at least one episode of grade 3-4 toxicity, most commonly anemia, neutropenia, fatigue, and neutropenic fever. 24 patients received more than 2 cycles. Median progression free survival was 1.6 months and median overall survival was 5 months. Figure 1

      Conclusion
      Response to second-line therapy with gemcitabine or vinorelbine is rare. The rate of stable disease suggests some level of activity of these agents. Therefore, it remains a reasonable standard therapeutic option. However, survival was comparable to the placebo arm in the phase III vorinostat trial (Krug, ECCO/ESMO, 2011). This lack of efficacy supports the use of placebo control arms in randomized second-line MPM trials. Novel therapies are desperately needed for this patient population.