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J.D. Patel



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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 - 10:00  |  Author(s): J.D. Patel

      • 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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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.12 - Efficacy and safety of paclitaxel and carboplatin with bevacizumab for the first-line treatment of patients with nonsquamous non-small cell lung cancer (NSCLC): analyses based on age in the phase 3 PointBreak and E4599 trials (ID 2879)

      17:20 - 17:25  |  Author(s): J.D. Patel

      • Abstract
      • Presentation
      • Slides

      Background
      A post hoc analysis of NSCLC patients (pts) aged ≥70 y in the pivotal E4599 trial found increased adverse events (AEs) and numerically decreased overall survival (OS) benefit associated with bevacizumab (BEV) compared with pts <70 y. We evaluated the efficacy and safety of BEV by age in pts in a pooled dataset from the E4599 and PointBreak (PB) trials.

      Methods
      Pts randomized to the PC (paclitaxel and carboplatin ) + BEV arms of E4599 and PB received P 200 mg/m[2], C AUC 6, and BEV 15 mg/kg q3w for 6 (E4599) or 4 (PB) cycles; Eligible pts received maintenance BEV alone q3w until disease progression or unacceptable toxicity. OS, progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and safety were assessed in pts grouped according to age (<65 y, 65–74 y, 70–74 y, <75 y, and ≥75 y). Pt-level data from the PC + BEV arms of E4599 and PB were pooled and compared with data from pts in the PC-alone arm of E4599.

      Results
      PB and E4599 randomized 467 pts and 434 pts to PC + BEV, respectively, while 444 were randomized to receive PC alone on E4599. Baseline characteristics were balanced between age groups. OS and PFS hazard ratios (HRs) and increases in grade ≥3 AEs for the pooled pt cohort relative to E4599 PC-alone arm are shown (Table). Outcomes were similar in pts <70 y and ≥70 y, and data from the pooled population were similar to those seen in each individual trial (data not shown). ORR for pts <75 y was 39% with PC + BEV vs 26% with PC (P<.01). For pts ≥75 y, ORR was 33% vs 30% (P=.71). DCR in pts <75 y was 70% with PC + BEV vs 53% with PC (P<.01). For pts ≥75 y, DCR was 60% vs 67% (P=.37).

      Conclusion
      In a pooled exploratory analysis of pt data from E4599 and PB, the statistically significant benefit associated with the addition of BEV to PC appeared consistent across all age groups <75y, while pts ≥75 y receiving PC + BEV had no statistically significant survival benefit. Pts receiving PC + BEV had an increase in grade ≥3 AEs compared with pts receiving PC-alone in all age groups.

      PB + E4599 <65 y n=735 65–74 y n=453 70–74 y n=203 <75 y n=1188 ≥75 y n=157
      HR for OS 95% CI P 0.75 0.62–0.89 <.01 0.80 0.64–1.00 .05 0.68 0.48–0.96 .03 0.78 0.68–0.89 <.01 1.05 0.70–1.57 .83
      HR for PFS 95% CI P 0.71 0.60–0.85 <.01 0.62 0.49–0.78 <.01 0.68 0.48–0.96 .03 0.69 0.60–0.79 <.01 0.95 0.62–1.44 .80
      E4599 n=499 n=277 n=129 n=776 n=102
      Δ Grade ≥3 AEs,[a ]% P 13 <.01 21 <.01 23 <.01 15 <.01 25 <.01
      [a]Relative to PC-alone arm.

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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P1.10-004 - Exploratory Subset Analysis in African Americans from the PointBreak Study (Randomized Phase 3 Pemetrexed + Carboplatin + Bevacizumab Followed by Maintenance Pemetrexed + Bevacizumab Versus Paclitaxel + Carboplatin + Bevacizumab followed by Maintenance Bevacizumab in Patients with Stage IIIB/ IV   Nonsquamous Non-Small Cell Lung Cancer) (ID 249)

      09:30 - 09:30  |  Author(s): J.D. Patel

      • Abstract

      Background
      African Americans (AA) have a higher rate of lung cancer than Caucasians per 100,000 population (74.7 versus 64.4) but are underrepresented in randomized clinical trials. In the PointBreak study, AAs were enrolled at the same rate as the US incidence of non-small cell lung cancer (NSCLC) for AAs in 2011 (13%; now 15% in 2013). Post-hoc analyses of the AA subgroup were conducted from this study to evaluate efficacy and safety, as well as these outcomes by treatment center.

      Methods
      All patients (N=939) were chemonaive with an ECOG performance status (PS) of 0/1. AAs were analyzed against Caucasians for efficacy/safety in the pemetrexed (Pem) arm only. Subgroup analyses of AAs alone were conducted for efficacy/safety (between arm comparisons) as well as academic versus community settings (pooled two treatment arms). Hazard ratios and p-values were derived from a multivariate Cox-PH model, adjusting for disease stage, gender, PS and measurable/nonmeasurable disease. Response rates and adverse events (AEs) were compared using the exact test.

      Results
      Patients had stage IIIb (with pleural effusion)/IV nonsquamous NSCLC, according to AJCC edition 6. There were 94 AAs (42 = Pem arm; 52 = Paclitaxel [Pac] arm) and 805 Caucasians in the treated population. Demographics were statistically comparable between AAs and Caucasians in the Pem Arm, respectively: 62%/53% male, 71%/53% ≤65 years, 98%/89% ever smokers, 81%/90% Stage IV disease, with ECOG PS of 0/1, 33%/67%, versus 44%/56%. Median OS was similar between AAs and Caucasians in the Pem arm at 12.4 versus 12.3 months. Median PFS for AAs and Caucasians was 4.6 months versus 6.0 months (HR 1.229 (0.864 – 1.749; p=0.251). Overall response rate (ORR) for AAs was higher, though not statistically, at 38.1% versus 33.3% (p=0.607). Efficacy among AAs was fairly similar with median OS for Pem arm at 12.4 versus 13.7 months for Pac arm (p=0.1208). Median PFS by arm was 4.6 versus 5.1 months (p=0.6699). ORR among AAs was 38% in both arms. AAs showed a heavy trend (80%) for enrollment in community centers (n=74) versus academic center (n=20). Efficacy among AAs by setting showed a higher median OS at academic sites at 16.5 months versus 11.4 months, p=0.1906 (HR=0.6605; 95% CI: 0.355 – 1.229). Median PFS was also higher at academic sites at 6.9 months versus 4.6 months, p=0.9149 (HR =0.9690; 95% CI: 0.544 – 1.726). Drug-related grade 3/4 AEs in the Pem arm showed higher percentages for Caucasians with the exception of neutropenia, as follows: anemia (7.3%/15.9%), thrombocytopenia (9.8%/25.5%), fatigue (4.9%/11.5%), neutropenia (31.7%/25.3%), febrile neutropenia (0%/1.6%). Among AAs in the Pem/Pac Arm respectively, drug-related grade 3/4 AEs were: anemia (7.3%/0%), thrombocytopenia (9.8%/4.0%), fatigue (4.9%/4.0%), neutropenia (31.7%/44.0%), and febrile neutropenia (0%/4.0%).

      Conclusion
      There were no significant differences between AAs and Caucasians for OS, PFS, and ORR. Among AAs, median OS was not superior for either arm. PFS and OS were similar for academic and community settings among AAs. Caucasians had a significantly higher incidence of Grade 3/4 thrombocytopenia (p=0.0217), but this should be interpreted with caution due to the sample size for the AAs.

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      P1.10-034 - Weight Gain as a Prognostic Factor on Patient Outcomes<br /> In Advanced, Nonsquamous, Non-small Cell Lung Cancer (ID 1905)

      09:30 - 09:30  |  Author(s): J.D. Patel

      • Abstract

      Background
      Patients with advanced/metastatic non-small cell lung cancer (NSCLC) have a poor prognosis and low survival rates. One of the first notable symptoms of advanced lung cancer is unexplained weight loss. We evaluated weight gain (> 5% post baseline), as an early prognostic factor for clinical outcome, in advanced nonsquamous, NSCLC patients.

      Methods
      This retrospective analysis reports on three randomized phase III studies with survival and response data from a total of 2301 advanced, nonsquamous NSCLC patients who received pemetrexed or other chemotherapy plus a platinum or targeted agent, as first-line therapy. Body weight was recorded before and after treatment by each study’s schedule. Baseline weight was defined as the last non-missing weight measure before first treatment. Post baseline weight was defined as the maximum weight measured after starting treatment. Patients were analyzed using log-rank test and adjusted Cox modeling to assess the relationship between weight gain and overall survival (OS) and progression-free survival (PFS). Logistic regression was used to assess the association between baseline covariates and post-baseline weight gain.

      Results
      Patients were a mean age of 61 years (range 26 – 86) and most were of Caucasian descent (77.0%). A majority of patients had adenocarcinoma (73.8%), were male (59.8%) with an ECOG performance status (PS) of 0/1/2 (38.5%/60.2%/1.4%). Many patients were smokers or former smokers (55.7%) with Stage IV disease (83.1 %), according to the American Joint Committee on Cancer, editions. 5/6 and had an average weight at baseline of 71.4 kg. A total of 421 (18.3%) patients had a >5% increase in weight (>5% subgroup) after baseline with a statistically significant increase in OS and PFS. Median OS was 16.7 months for patients in the >5% subgroup versus 10.7 months for patients who gained <5% weight (< 5% subgroup; [n=1880]; p<0.001). PFS was 6.9 months for the >5% subgroup versus 4.8 months for <5% subgroup; p<0.001). Differences in overall response rate (ORR = CR + PR) and disease control rate (DCR = CR + PR + SD) were also significant. ORR was 50.8% for >5% subgroup versus 25.4% for < 5% subgroup (p<0.001). DCR was 91.5% for >5% subgroup and 63.6% for <5% subgroup (p<0.001). Cox modeling revealed patients in the >5% subgroup had significantly longer survival (HR=0.56, [95% CI 0.49-0.64]; p<0.001) than patients with <5% subgroup, after adjusting for baseline age (<65 versus 65), sex, ECOG PS (0 versus 1/2), histology (adenocarcinoma versus others), and study. Similar significant results were also found for PFS. Logistic regression indicated a significant association between weight gain and age. More patients aged <65 had a >5% weight gain (p<0.001).

      Conclusion
      This exploratory analysis showed that substantial weight gain (>5%) occurred after initiation of platinum-based chemotherapy in approximately 20% of advanced/metastatic, nonsquamous NSCLC patients. There was a positive correlation between weight gain and improved, OS, PFS and response in patients treated in these phase III studies.

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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
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      P2.11-006 - Review of 10 Years of ASCO Abstracts for Non-Small Cell Lung Cancer (NSCLC) and the Impact of Molecular Biomarkers (MB) in Clinical Trial Selection Criteria (ID 901)

      09:30 - 09:30  |  Author(s): J.D. Patel

      • Abstract

      Background
      Over the last decade, incorporation of new cytotoxic chemotherapeutics, introduction of maintenance therapy, and integration of targeted therapies have altered treatment paradigms for patients with metastatic NSCLC (mNSCLC). In a disease that was largely treated empirically, therapy is now tailored based upon histology and MB. We sought to analyze whether outcomes of clinical trials in mNSCLC reported over 10 years at the ASCO Annual Meeting reflected perceived gains in the treatment of patients with mNSCLC.

      Methods
      Data were collected from ASCO abstracts of Phase II–IV clinical trials for patients with mNSCLC from 2004–2013. Trials in Progress abstracts were excluded. Data collected included author names, histology and MB selection criteria, phase, primary endpoint, outcomes, and drugs used. We hypothesized that rates of positive clinical trial outcomes would increase over time and that trials using MB selection criteria would have higher rates of positive outcomes. Statistical comparisons were made using Fisher’s exact test with two-sided p-values. Trends were compared using Spearman’s rank correlation.

      Results
      711 of 2,540 identified mNSCLC category abstracts met selection criteria. Over 50% were published by the top 10% of 841 unique first/last authors. Annual abstracts fitting selection criteria declined from 107 to 41 from 2004–2013. Common primary endpoints were: not specified (31%), response rate (24%), progression-free survival (PFS, 22%), and overall survival (OS, 14%). Few phase II trials had primary endpoints of PFS or OS (20.4%, 6.0%). The proportion of trials with positive PFS outcomes increased from 3.7% to 26.8% despite decreases in total annual abstracts (correlation coefficient = –0.67, p=0.033) (see Figure). Positive OS outcomes increased from 0.9% to 4.9%. Trials with MB selection criteria (5.6%) or non-squamous (NS) histology (13% of trials without MB selection) increased from 0% to 22% and 18% annually, respectively, and were more likely to result in an improvement in PFS (20.0% vs. 9.2%, p=0.0482 and 23.0% vs. 7.3%, p=0.0001, respectively). These criteria had no significant association with OS or QOL outcomes. Figure 1

      Conclusion
      Despite fewer phase II–III clinical trials presented at ASCO annually, there was a significant increase in those with positive PFS outcomes. Increases in trials selective for MB or NS histology may account for the improved PFS results. These data suggest better trial design and efficient use of resources. These data may also reflect bias in selecting abstracts for presentation, which could result in missed learning opportunities for future trial design. Additionally, it is unclear whether PFS endpoints are as meaningful as OS.