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G. Riely



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

    • Event: WCLC 2013
    • Type: Exhibit Showcase Session
    • Track:
    • Presentations: 1
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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): G. Riely

      • 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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    MO07 - NSCLC - Targeted Therapies II (ID 114)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO07.03 - Crizotinib therapy for patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC) (ID 2777)

      16:15 - 17:45  |  Author(s): G. Riely

      • Abstract
      • Presentation
      • Slides

      Background
      Rearrangements of the ROS1 receptor tyrosine kinase gene identify a subset of NSCLC sensitive to the small-molecule ALK and MET inhibitor crizotinib, approved multinationally for the treatment of advanced ALK-positive NSCLC. Here we present updated efficacy and safety data for crizotinib in an expanded cohort of patients with advanced ROS1-rearranged NSCLC.

      Methods
      ROS1 status was determined by break-apart FISH assays, and patients were enrolled into an expansion cohort of an ongoing phase I crizotinib study (PROFILE 1001; NCT00585195, Pfizer). Where available, samples were also tested for concurrent ALK rearrangement and MET amplification. Patients received crizotinib 250 mg BID, and responses were assessed using RECIST v1.0.

      Results
      At the data cut-off, 35 of 40 patients with ROS1-positive NSCLC were evaluable for response. Median age was 51 years (range 31–77), 80% of patients were never-smokers, and 98% had adenocarcinoma histology; 40% had received one prior regimen, and 45% had received 2–6 regimens for advanced/metastatic disease. 25 samples tested for concurrent ALK rearrangement (24 by FISH and 1 by PCR) and 12 samples tested for concurrent MET amplification (11 by FISH and 1 method not recorded) were all negative. The objective response rate (ORR) was 60% (95% CI: 42–76), with 2 complete responses, 19 partial responses, and 10 cases of stable disease. Median progression-free survival (PFS) had not been reached, with 25 patients (63%) still in follow-up for PFS; six patients (15%) experienced disease progression, and two (5%) died before progression occurred; 6-month PFS probability was 76% (95% CI: 55–88). The disease-control rate was 80% at 8 weeks and 66% at 16 weeks. The most common treatment-related adverse events (AEs) were visual impairment (80%), diarrhea (35%), and nausea (30%), with most patients (68%) reporting only AEs of grade 1 or 2 severity. Peripheral edema (28%) and elevated transaminases (18% AST, 15% ALT) were also reported, similar to previous experience with crizotinib. There were no treatment-related serious AEs and one patient discontinued treatment due to treatment-related nausea. Accrual of patients with ROS1-positive NSCLC is ongoing.

      Conclusion
      Similar to results obtained in ALK-positive NSCLC, crizotinib had marked antitumor activity with a high ORR (60%) in patients with ROS1-positive NSCLC, with a generally tolerable and manageable AE profile. These data suggest that crizotinib is an effective therapy for patients with advanced ROS1-positive NSCLC.

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    O16 - NSCLC - Targeted Therapies III (ID 115)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 2
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      O16.06 - A phase 1 dose escalation study of a new ALK inhibitor, CH5424802/RO5424802, in ALK+ Non-Small Cell Lung Cancer (NSCLC) patients who have failed crizotinib (AF-002JG/NP28761, NCT01588028). (ID 1661)

      10:30 - 12:00  |  Author(s): G. Riely

      • Abstract
      • Presentation
      • Slides

      Background
      Anaplastic lymphoma kinase (ALK) is a tyrosine kinase constitutively activated following chromosomal translocation in 3-7% of non-small cell lung cancer (NSCLC). These patients usually respond to the ALK inhibitor crizotinib with a median duration of response around 10 months. CH5424802 is a more potent and specific ALK inhibitor that is being studied as a treatment for NSCLC patients with ALK gene rearrangement.

      Methods
      A phase 1 dose escalation study of CH5424802 was performed using 3+3 study design in NSCLC patients who failed crizotinib. The primary endpoint was dose limiting toxicity, and the secondary endpoints were efficacy, safety and pharmacokinetic (PK) analyses. Key eligibility criteria include prior progression on crizotinib, ECOG 0-2, adequate organ functions, confirmed ALK-rearrangement by an FDA approved test. Patients with symptomatic CNS metastases required treatment before participating. CH5424802 was administered orally at doses of 300, 460, 600, 760 and 900 mg BID until lack of clinical benefits. Intensive PK sampling was performed. Efficacy was assessed by RECIST criteria v1.1. Toxicities were evaluated by CTCAE v4.0.

      Results
      37 NSCLC patients who have failed crizotinib and chemotherapy were enrolled in the study from 6 US sites from May 2012 to May 2013. No DLTs were observed up to the highest dose tested (900 mg BID). Only 1 patient required dose modification due to grade 2 fatigue. The most common AEs were fatigue, CPK increase, myalgia, cough, ALT increased, peripheral edema and rash. Grade 3/4 AEs include GGT increase (n=3), neutrophil decrease (n=2), hypophosphatemia, hyperglycemia, syncope, renal failure and pericardial effusion (n=1 each), but no grade 3 nausea, vomit, diarrhea, edema were reported. Preliminary efficacy was observed with PR 48% and SD 34% by investigator assessment amongst the 30 evaluable patients (See Figure of Waterfall plot). Median progression-free survival has not been reached with 27 patients (73%) remaining on study as of June 10, 2013 (median duration 85 days, range 39-347+ days). CNS activity was observed and described in the companion abstract by Ou et al. CH5424802 single dose half-life was approximately 22 hr, AUC was dose-dependent from 300 to 600 mg BID following multiple doses with a potential plateau at doses higher than 600 mg BID based on available data.Figure 1

      Conclusion
      CH5424802 is a well-tolerated ALK inhibitor with no DLTs observed up to the highest dose tested in this study. Promising anti-tumor activity was observed in patients who have failed crizotinib.

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      O16.07 - Consistent therapeutic efficacy of CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer (NSCLC) patients in an ongoing phase I/II study (AF-002JG/NP28761, NCT01588028). (ID 1668)

      10:30 - 12:00  |  Author(s): G. Riely

      • Abstract
      • Presentation
      • Slides

      Background
      Disease progression in brain occurs in ~50% ALK-rearranged NSCLC patients treated with crizotinib. This is likely due in part to low penetration of crizotinib into CNS. CH5424802 is a new ALK inhibitor that is effective in patients who have ALK re-arrangement. Preclinical studies in CNS implantation models suggest a promising anti-tumor activity of CH5424802 against CNS lesions. This report describes CNS activity observed in an ongoing phase I/II clinical trial.

      Methods
      A phase I dose escalation study of CH5424802 was performed in ALK-rearranged NSCLC who have failed crizotinib. Patients received oral CH5424802 doses ranging from 300 to 900 mg BID. All patients had head CT/MRI and body CT scans at baseline, and every 6 weeks after initiation of treatment if baseline scans are positive for brain metastasis. Brain lesions without prior radiation were used to assess CNS response based on modified RECIST criteria. Simultaneous collection of cerebrospinal fluid (CSF) and plasma PK samples in selective patients is ongoing to evaluate CSF/plasma CH5424802 ratios to correlate with clinical activity in brain metastasis.

      Results
      As of June 6, 2013, 37 patients were enrolled in the phase I study, and 31 of them were evaluable for efficacy. Preliminary overall response rate (ORR) is ~48% (15/31) in evaluable patients. 16 had brain metastases at baseline, and 2 had no prior brain irradiation but all had documented CNS progression prior to study treatment. These 16 patients received CH5424802 at 300mg (n=2), 460mg (n=2), 600mg (n=5), 760mg (n=3), and 900mg (n=4) BID. The median duration of follow-up of these 16 patients was 130+ days, with the longest being 347+ days. Activity against CNS lesions was observed as early as the first scan (3[rd] week). The preliminary CNS response is highly promising as shown in the representative scans below. Enrollment is still ongoing and CNS progression-free survival (PFS) will be presented. Currently 2 patients had simultaneous CSF and plasma levels of CH5424802, and the CSF/plasma ratios will be reported to evaluate any correlation between CSF/plasma ratios and the observed clinical activity of CH5424802 in brain metastasis.Figure 1

      Conclusion
      CH5424802 demonstrates consistent and rapid clinical activity in brain metastases in ALK+ NSCLC patients who progressed on crizitinib. Within 3-6 weeks of treatment, CH5424802 dramatically shrinks brain lesions that progressed on crizotinib. CH5424802 could potentially replace or delay the need of brain radiation in ALK-positive NSCLC patients.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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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): G. Riely

      • 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.

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      P2.11-026 - RET Fusion-Positive Advanced Lung Cancers: Response to First-Line Chemotherapy and Survival in Comparison to ROS1 and ALK Fusion-Positive and EGFR- and KRAS-Mutant Lung Cancers (ID 1964)

      09:30 - 16:30  |  Author(s): G. Riely

      • Abstract

      Background
      RET fusions are novel targetable drivers in non-small cell lung cancers. While the clinicopathologic profile of patients with RET fusion-positive tumors has been described in early-stage disease, little is known regarding clinical behavior in advanced unresectable disease.

      Methods
      Patients with advanced unresectable (stage IIIB/IV) pan-negative lung adenocarcinomas (absence of mutations in EGFR, KRAS, NRAS, BRAF, MAP2K1, ERBB2, PIK3CA, and AKT, and fusions of ALK or ROS1) were screened for RET fusions via dual-probe break apart FISH testing. Upstream partners were identified via RT-PCR and next-generation sequencing whenever possible. A retrospective review of patient records was conducted to determine response to systemic therapy and overall survival (OS). OS was calculated from diagnosis of metastatic disease and compared to patients with ALK and ROS1 fusion-positive, and EGFR- and KRAS-mutant lung cancers. Survival curves were estimated using the Kaplan-Meier method. Differences in survival between groups were assessed by the log-rank test.

      Results
      A RET fusion was found in 16% (n=12/76, 95%CI 8%-24%) of pan-negative tumors and 19% (n=10/48, 95%CI 10%-33%) of pan-negative tumors from never-smokers. Patients with RET fusion-positive tumors were predominantly never-smokers (83%, n=10/12, 2 patients with 7 and 10 pack-year histories, respectively) with advanced-stage disease at diagnosis (92%, n=11/12 stage IIIB/IV). Fusion partners were identified in 6 patients (4 KIF5B-RET, 1 TRIM33-RET, 1 NCOA4-RET). Eight patients (67%) received first-line platinum-based therapy, 6 of whom (50%) received maintenance pemetrexed and/or bevacizumab. Partial responses (PRs) were seen in 3 patients (38%) and stable disease (SD) in 5 patients (62%). 1-year OS on chemotherapy and median progression-free survival were 47% and 7.3 months, respectively. 1-year and 2-year OS for patients whose tumors harbored RET, ROS1, or ALK fusions, or EGFR or KRAS mutations is summarized below (Table). OS was not significantly different between RET, ROS1, ALK, or EGFR cohorts when RET was compared to each of the latter three cohorts separately. The presence of a RET fusion was associated with improved OS compared to the presence of a KRAS mutation (HR 0.39, 95%CI 0.21-0.74, p=0.004). Of the 11 patients with RET fusion-positive lung cancers, 4 patients (36%) were treated with cabozantinib on a phase 2 protocol (NCT01639508) with disease shrinkage of -66%, -32%, -23%, and -19% via RECIST v1.1.

      Driver Detected OS 1-year [95%CI] OS 2-year [95%CI]
      RET (n=12) 100% 71% [25%-92%]
      ROS1 (n=9) 88% [39%-99%] 88% [39%-99%]
      ALK (n=44) 91% [77%-97%] 73% [55%-85%]
      EGFR (n=102) 85% [76%-91%] 58% [47%-67%]
      KRAS (n=117) 60% [50%-66%] 26% [18%-35%]

      Conclusion
      Response to platinum-based first-line therapy in patients with RET fusion-positive tumors is comparable to historical controls. Survival in patients with RET fusion-positive disease is comparable to patients with EGFR mutations and other recurrent gene fusions (ROS1 and ALK) and improved compared to patients with KRAS mutations. Cabozantinib is worthy of further study in RET fusion-positive lung cancers.