Author of

• 12012

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  Best of Posters - IASLC Selection - Part 1 (ID 262)

  • Event: WCLC 2013
  • Type: Exhibit Showcase Session
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:55 - 10:25, Exhibit Hall, Ground Level

  • 10809

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    P1.11-008 - A phase II study of HSP90 inhibitor AUY922 and erlotinib (E) in patients (pts) with EGFR-mutant lung cancer and acquired resistance (AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs). (ID 976)

    09:55 - 10:25  |  Author(s): H.A. Yu
    • Abstract
    • Slides

    Background
    AUY922 is an HSP90 inhibitor that degrades client onco-proteins including mutant EGFR. Preclinical studies utilizing cell lines and xenografts harboring EGFR T790M demonstrate that HSP90 inhibition is effective in models of AR. This phase II study combines AUY922 and E for the treatment of patients with EGFR-mutant lung cancer and RECIST-progression on EGFR TKIs.

    Methods
    Eligible patients had EGFR mutations and developed AR (per Jackman, JCO 2010) after treatment with EGFR TKIs. Patients underwent tumor biopsies after developing AR and prior to study entry. Tumor tissue from re-biopsy was analyzed for EGFR T790M and other mechanisms of resistance. Patients received AUY922 70 mg/m[2 ]IV weekly and E 150 mg oral daily in 28-day cycles. Response assessment was done at 4 weeks (wks), 8 wks, and every 8 wks thereafter. The primary objective was overall response rate (ORR, CR+PR) at 8 wks. A Simon mini-max design determined sample size (stage I: 16 pts (≥2 responses needed to proceed to stage II), stage II: 9 pts; α=10%, β=10%, p0=10%, p1=30%).

    Results
    The trial has completed accrual, and twenty-five patients have been treated (18 women, median age 59 (range 42-76)). The median time on EGFR TKI prior to the development of AR was 11 mo (range 3-26 mo). Ten patients (40%) had EGFR T790M identified by tumor re-biopsy. In the 25 patients evaluable for response, ORR was 4/25 (16%, 95% CI 6-35%). Three of four patients with PR had EGFR T790M. An additional four patients had stable disease for at least 8 weeks. To date, four patients were on study drug for ≥ 4 cycles, and four patients currently remain on study. Adverse events reported in ≥ 20% of patients were diarrhea, fatigue, myalgias, nausea, mucositis, and night blindness. Sixty-eight percent (17/25) experienced night blindness (grade 1-2 only), and three patients came off study due to eye-related toxicity. Grade 3 toxicities included elevated liver function tests, diarrhea, fatigue, constipation and anemia.

    Conclusion
    AUY922 and E is an active, well-tolerated regimen for patients with EGFR-mutant lung cancer. Visual disturbances, particularly night blindness, were common, but resolved with drug discontinuation. AUY922 and erlotinib demonstrate activity as combination therapy for patients with EGFR mutant lung cancers and AR to EGFR TKI. Activity is not limited to patients with EGFR T790M. Supported by Novartis, Inc.

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• 10583

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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
  • Moderators:
  • Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 10642

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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): H.A. Yu
    • 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.

• 11745

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  P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Medical Oncology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11770

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    P2.11-025 - Erlotinib versus Radiation Therapy for Brain Metastases in Patients with EGFR-Mutant Lung Adenocarcinoma (ID 1904)

    09:30 - 16:30  |  Author(s): H.A. Yu
    • Abstract

    Background
    Radiation therapy (RT) is a principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in the central nervous system, it is uncertain whether upfront brain RT is necessary for EGFR mutated lung adenocarcinoma patients with BM treated with EGFR-TKIs.

    Methods
    We identified all patients treated from 2006-2012 with EGFR-mutated NSCLC with BM at our institution. We evaluated the clinical outcomes of these patients who developed brain metastases and received EGFR-TKI and/or CNS radiotherapy. Endpoints included intracranial progression (ICP), extracranial progression (ECP) and overall survival (OS). All endpoints were measured from development of BM.

    Results
    222 patients were identified. Patients were excluded if they were on an EGFR-TKI prior to the development of BM (n=57), if they possessed a de novo EGFR-TKI resistance mutation (n=6), or if there was incomplete data (n=48). Of the remaining 111 patients, 64 were treated initially with erlotinib, 32 with whole brain RT (WBRT), and 15 with partial brain radiation (PBI). Median follow-up was 20 months (mos). Median age was 61 years (range 26-89). Patients were predominantly female (68%), stage IV at diagnosis (92%), never-smokers (61%), RPA class II (87%), and neurologically asymptomatic (82%). Patients had a median of 4 BM (range 1-30) with a median largest diameter of 10mm. In the erlotinib group, erlotinib was given as monotherapy in 91% and combined with chemotherapy in 9% of patients. 38% of these patients (n=24) eventually received WBRT or PBI a median of 17 mos after diagnosis of BM (range 5-40 mos). Median OS for the whole cohort was 29 mos with a 2-yr OS of 59%. There was no significant difference in OS between the WBRT (median 35 mos) and erlotinib (median 26 mos) groups (p=0.59 by Cox model) though patients treated with PBI had a longer OS (median 64 mos). On univariate analysis, KPS (p<.001), RPA class (p<.001) and PBI (vs. erlotinib, p=.005) were significant, with only RPA class (p=.007) and KPS (p<.001) remaining significant on multivariate analysis. Median time to intracranial progression (ICP) was 17 months for the entire cohort. There was a longer time to ICP in patients who received WBRT (median 24 mos) vs. erlotinib upfront (median 16 mos, p<.05), though this effect was no longer significant on multivariate analysis. Patients in the erlotinib or PBI group were more likely to fail intra-cranially as a component of first failure (58% and 71%, respectively), while upfront WBRT patients were more likely to fail extracranially first (76%).

    Conclusion
    The survival of EGFR-TKI naïve patients with EGFR-mutated NSCLC with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, but this effect is potentially due to other confounding variables. Though retrospective, this analysis suggests that deferring brain RT in favor of EGFR-TKI is a reasonable strategy for patients with EGFR-mutated NSCLC with BM.