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M.C. Pietanza



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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): M.C. Pietanza

      • 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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    MO13 - SCLC I (ID 118)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO13.10 - Prospective Molecular Evaluation of Small Cell Lung Cancer (SCLC) Utilizing the Comprehensive Mutation Analysis Program at Memorial Sloan-Kettering Cancer Center (MSKCC) (ID 3137)

      10:30 - 12:00  |  Author(s): M.C. Pietanza

      • Abstract
      • Presentation
      • Slides

      Background
      Oncogenic events in adenocarcinoma and squamous cell cancers of the lung are well described. In contrast, the repertoire of possible molecular targets in SCLC still is unclear. Recent studies using next generation sequencing on rare resected SCLC specimens have provided insights into the molecular heterogeneity of this disease. Comprehensive, prospective molecular profiling of patients with SCLC using the biopsy specimens available in clinical practice has not been performed.

      Methods
      Utilizing an IRB-approved protocol to prospectively test SCLC tumors (Small Cell Lung Cancer Mutation Analysis Program, “SCLC-MAP”), these biopsies are evaluated by: FISH for FGFR1 and MET amplification; immunohistochemistry (IHC) for MGMT and PTEN loss; point mutation genotyping with Sequenom for PIK3CA (and others); and next-generation sequencing with our MSK-IMPACT assay (Integrated Mutation Profiling of Actionable Cancer Targets). MSK-IMPACT uses exon capture followed by massively parallel sequencing to profile all protein-coding exons and select introns of 279 cancer-associated genes, enabling the identification of mutations, indels, and copy number alterations of these genes. First, we tested the feasibility of this approach in a series of SCLC patients that were identified retrospectively as they had banked matched tumor and normal pairs. We performed next generation sequencing with MSK-IMPACT, with findings confirmed by FISH on these samples. We are prospectively collecting and evaluating SCLC tumors of our patients in active treatment, as detailed above.

      Results
      For our feasibility cohort, we identified 21 patients with SCLC with FFPE samples available from both matched normal tissue and small tumor biopsies. After histologic review and DNA extraction, 10 patients had adequate tissue for MSK-IMPACT (3 core biopsies, 7 fine needle aspirates). The following were noted: recurrent mutations in Rb1 (N=7) and p53 (N=8), FGFR1 amplification (N=2), and MET amplification (N=1), using as little as 15 nanograms of DNA. FGFR1 and MET amplification were confirmed by FISH testing. We have initiated this prospective SCLC-MAP program for our SCLC patients undergoing active treatment. Since 2/2013, 25 patients have provided consent and tumor tissue for analysis (8 surgical resections, 12 core biopsies, 3 lymph node dissections, 2 fine needle aspirates). Preliminary data are available for 16 patients: AKT1 E17 mutation by Sequenom (N=1), MGMT loss by IHC (N=1); and PTEN loss by IHC (N=2).

      Conclusion
      As adequate biopsy specimens are necessary to match lung cancer patients and treatments, increased number of patients with SCLC are presenting with more tissue. Comprehensive molecular evaluation of SCLC is feasible on clinically available specimens, as seen in our feasibility cohort. Prospective collection of SCLC tumor samples and mutational analyses are ongoing. Such analyses will allow us to characterize the molecular diversity of this disease and identify patients who will be candidates for targeted therapies. Funded, in part, by the Lung Cancer Research Foundation.

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