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M. Tehfe



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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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      MO06.08 - A phase 2 randomized open-label study of ramucirumab (IMC 1121B; RAM) in combination with first-line platinum-based chemotherapy in patients (pts) with recurrent or advanced non-small cell lung cancer (NSCLC): final results from non-squamous (NSQ) pts (NCT01160744) (ID 1471)

      16:55 - 17:00  |  Author(s): M. Tehfe

      • Abstract
      • Presentation
      • Slides

      Background
      Vascular endothelial growth factor (VEGF)-mediated angiogenesis plays an important role in NSCLC pathogenesis. RAM is a human IgG1 monoclonal receptor targeted antibody that inhibits VEGF receptor-2 (VEGFR-2) binding and signaling. This study investigates RAM in combination with first-line platinum-pemetrexed chemotherapy in advanced NSCLC.

      Methods
      Eligible patients had Stage IIIb/IV NSCLC, ECOG PS ≤ 2, and no prior chemotherapy or VEGF/VEGFR therapy for metastatic disease. Non-squamous (NSQ) pts with advanced NSCLC were randomized 1:1 to either Arm A: pemetrexed + carboplatin/cisplatin (PEM + Cb/Cis) followed by PEM maintenance or Arm B: Ramucirumab 10 mg/kg + pemetrexed + carboplatin or cisplatin (RAM + PEM + Cb/Cis), followed by RAM + PEM maintenance once every 3 weeks. Patients received the first-line therapy from 4 to 6 cycles (21-day cycle); patients without evidence of disease progression entered a maintenance phase. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), change in tumor size, duration of response, and safety.

      Results
      From Oct 2010 to 2012, 140 pts were randomized (PEM + Cb/Cis: 71; RAM + PEM + Cb/Cis: 69). Overall, baseline patient characteristics were balanced between arms. The median PFS was 5.6 m PEM + Cb/Cis and 7.2 m for RAM + PEM + Cb/Cis; HR 0.75 (90% CI, 0.55, 1.03; p =0.132). ORR (CR + PR) was 38% for PEM + Cb/Cis and 49.3% including one complete response in the RAM + PEM + Cb/Cis arm (p=0.18). Disease control rate (CR + PR + SD) was 70% PEM + Cb/Cis and 86% for RAM + PEM + Cb/Cis ( p = 0.031). Median OS at the time of final PFS analysis was 10.4 m for PEM + Cb/Cis and 13.9 m for RAM + PEM + Cb/Cis; HR 0.83 (90% CI, 0.56, 1.22; p=0.43). Grade ≥ 3 adverse events (AEs) occurring in >10% of patients on RAM containing arm were: anemia, neutropenia, thrombocytopenia, nausea, fatigue, back pain, and hypertension.

      Conclusion
      While the primary endpoint of significant prolongation of PFS was not met, RAM has evidence of clinical activity in combination with PEM + Cb/Cis in patients with NSQ NSCLC. Addition of RAM to PEM + Cb/Cis did not result in excessive or unexpected toxicity.

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    P1.18 - Poster Session 1 - Pathology (ID 175)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P1.18-021 - Retrospective analysis of the prevalence of NSCLC driver mutations in unselected samples. (ID 3365)

      09:30 - 09:30  |  Author(s): M. Tehfe

      • Abstract

      Background
      Much of the recent improvement in lung cancer outcomes owes to the advent of the Lung Cancer Mutation Consortium. We aimed to assess thequality of the pathologic specimens and to study the prevalence of each of the most clinically relevant driver mutations in a non-referred population with non-squamous, non-small cell lung cancer (NS-NSCLC) treated in a tertiary center in the province of Quebec characterized by a high prevalence of smokers (25% of adult population).

      Methods
      Consecutive patients with pathologically proven NS-NSCLC diagnosed or treated in our institution between January 2006 and June 2009 inclusively were accrued. Patients whose diagnosis is based uniquely on a positive cytology or whose diagnostic material was not available were excluded. Specimens were tested for ALK translocations (by IHC and FISH), for EGFR mutations in exons 19 and 21 by PCR (fragment analysis and qPCR) and for mutations in KRAS codons 12 and 13 by PCR-RFLP. ALK-FISH and ALK-IHC results were analyzed in a blinded manner.

      Results
      A total of 1017 consecutive patients were screened. We excluded 209 patients who had only cytologic material, 55 patients who had no residual material and 197 patients who had insufficient tissue. Analysis was possible on 556 patients. The median age of the analyzed population was 64 years and male gender frequency was 45.5%. Compared to our entire cohort, metastatic cases were significantly under-represented in the analyzed population 27.3% vs. 79.1% for local disease (p<0.0001). The distribution according to stage and year of diagnosis along with that related to overall eligible population as well as the percentage of each of the 3 driver mutations status in the specimens analyzed so far are shown in the table below:

      Local disease analyzable / overall Loco-regional analyzable / overall Metastatic analyzable / overall Total analyzable / overall
      2006 - 2007 188/227 (82.8%) 66/147 (44.9 %) 55/207 (26.6 %) 311/583 (53.3 %)
      2008 - Mid 2009 161/214 (75.2%) 50/96 (52.1 %) 36/126 (28.6 %) 247/436 (56.7 %)
      Total 349/441 (79.1%) 116/243 (47.7%) 91/333 (27.3 %) 556/1017 (54.7 %)
      Mutation results: Local disease positive/total analyzed Loco-regional positive/total analyzed Metastatic positive/total analyzed Total positive/total analyzed
      KRAS codon 12 76/216 (35.2%) 20/55 (36.4%) 17/54 (31.5%) 113/325 (34.8%)
      KRAS codon 13 7/216 (3.2%) 2/55 (3.6%) 2/54 (3.7%) 11/325 (3.1%)
      KRAS mutated 83/216 (38.4%) 22/55 (40%) 19/54 (35.2%) 124/325 (37.9%)
      EGFR exon 19 11/128 (8.6%) 2/42 (4.8%) 4/39 (10.3%) 17/209 (8.1%)
      EGFR exon 21 6/128 (4.7%) 3/42 (7.1%) 1/39 (2.6%) 10/209 (4.8%)
      EGFR mutated 17/128 (13.3%) 5/42 (11.9%) 5/39 (12.8%) 27/209 (12.9%)
      ALK-FISH 2/264 (0.8%) 0/90 (0%) 1/69 (1.4%) 3/423 (0.7%)
      ALK – IHC* 1/277 (0.4%) 0/97 (0%) 1/75 (1.3%) 2/453 (0.4%)
      *One ALK-FISH positive case was IHC negative on repeated testing.

      Conclusion
      Our study shows that adequate tumor sampling is a challenge when performing retrospective molecular biology studies, creating a bias of adequate tissue availability in favor of more localized stages of disease. Nonetheless, our study shows a lower percentage of EGFR/ALK mutations and a higher percentage of KRAS mutations than that reported by the LCMC and other groups. This may be related to the non-selected, regional distribution and smoking habits of our study population. Prospective studies on the molecular diagnosis of NS-NSCLC will refine epidemiologic features of the different genetic subtypes of this disease.