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S.N. Waqar



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    MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      MA11.07 - Improved Small Cell Lung Cancer (SCLC) Response Rates with Veliparib and Temozolomide: Results from a Phase II Trial (ID 5517)

      15:02 - 15:08  |  Author(s): S.N. Waqar

      • Abstract
      • Presentation
      • Slides

      Background:
      PARP1 is overexpressed in small cell lung cancer (SCLC) and represents a novel therapeutic target for this disease. Preclinical data indicates that combining veliparib (an oral PARP-1/2 inhibitor) and temozolomide (TMZ) results in synergistic tumor growth delay or regression. In this study, we investigated whether adding veliparib to TMZ would improve outcomes in patients with relapsed sensitive and refractory SCLCs. Candidate predictive biomarkers, including SLFN11, were then explored.

      Methods:
      SCLC patients previously treated with 1 or 2 prior regimens were enrolled in the trial and randomized 1:1 to receive oral TMZ 150-200mg/m[2]/day (D1-5) with either veliparib or placebo 40mg twice daily, orally (D1-7) (NCT01638546). Primary endpoint was 4-month progression free survival (PFS). Data were analyzed in patients with platinum sensitive (progression >60 days after 1st line therapy) or refractory disease (progression ≤60 days after 1st line therapy, or in need of 3rd line treatment). Archived tissue was available for 53 patients for biomarker analysis.

      Results:
      104 patients were enrolled and 100 patients were treated. Baseline characteristics were balanced between treatment arms: 52% female; median age 62.5 (range, 31-84); 59% refractory disease; 33% needing 3rd-line therapy. Progression free survival at 4-months was similar between the two arms, 36% vs. 27% (p=0.39). However, in 93 evaluable pts, response rate was significantly higher in pts treated with veliparib/TMZ compared to TMZ alone (39% vs 14%, p =0.016). Median overall survival: 8.2 mos (95% CI: 6.4-12.2) in veliparib arm and 7 mos (95% CI: 5.3-9.5) in placebo arm, p = 0.50. Grade 3/4 thrombocytopenia and neutropenia more commonly occurred in the veliparib/TMZ arm: 50% vs 9% and 31% vs 7%, respectively. Levels of SLFN11, a marker of SCLC response to PARP inhibition in preclinical models, were assessed by immunohistochemistry. High SLFN11 in patient tumors (obtained at original diagnosis) was associated with a trend towards better overall survival in the veliparib/TMZ arm, but no difference in outcome in the TMZ alone arm. Additional correlative studies are ongoing, including assessment of MGMT promoter methylation, and will be available at the time of presentation.

      Conclusion:
      The combination of veliparib/TMZ increased response rates significantly, compared to TMZ alone. Hematologic toxicities of the combination may have impacted PFS (which was not significantly different between the arms) by limiting dosing. Biomarkers such as SLFN11, ATM, or MGMT promoter methylation could potentially help guide patient selection in the SCLC population.

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    P1.05 - Poster Session with Presenters Present (ID 457)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Early Stage NSCLC
    • Presentations: 1
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      P1.05-047 - Early Mortality in Patients with Non-Small Cell Lung Cancer Undergoing Adjuvant Chemotherapy (ID 5523)

      14:30 - 14:30  |  Author(s): S.N. Waqar

      • Abstract

      Background:
      Although adjuvant chemotherapy improves survival in patients with completely resected non-small-cell lung cancer (NSCLC) compared to surgery alone, it is also associated with potentially disabling or lethal adverse events. Since there is limited information on the early mortality among patients undergoing adjuvant chemotherapy, we used the National Cancer Data Base (NCDB) to calculate the percentage of deaths within the first 6 months from starting chemotherapy.

      Methods:
      The NCDB was queried for patients aged 18 or older, diagnosed with stage IB to IIIA NSCLC (AJCC 7[th] edition) from 2004 to 2012, who underwent surgery with negative margins followed by multi-agent chemotherapy, starting within 120 days from the surgical resection. Patients who received radiation therapy were excluded. Age groups were divided into <50, 51-60, 61-70, 71-80 and >80 years. Early mortality from months 1 to 6 were calculated and multivariate logistic regression was performed to identify clinical variables independently associated with mortality at six months from the date of initiation of adjuvant chemotherapy.

      Results:
      A total of 19,791 patients met the eligibility criteria. The median age was 65 (range 19-89). The percentage of deaths at 1, 2, 3, 4, 5 and 6 months were 0.6%, 1.3%, 1.9%, 2.6%, 3.3% and 4.2% respectively. The percentages of death at 6 months for each age group from < 50 years to > 80 years were 2.7%, 3.2%, 4.1%, 5.3% and 7.8% respectively. Factors independently associated with increased 6-month mortality included increased age, male gender, higher Charlson-Deyo co-morbidity score (CDCS), type of surgery, length of stay (LoS) > 6 days and 30-day readmission (Table).

      Conclusion:
      There is a high risk for early mortality among patients undergoing adjuvant chemotherapy for NSCLC, particularly in patients older than 70, with high co-morbidity score and a more complicated post-operative period.

      Table. Multivariable analysis
      Variable OR (95% CI) P-value
      Age
      ≤ 50 Reference Reference
      51-60 1.08 (0.74-1.60) 0.68
      61-70 1.33 (0.91-1.95) 0.15
      71-80 1.59 (1.06-2.38) 0.03
      > 80 2.27 (1.29-3.98) 0.004
      Gender
      Male Reference Reference
      Female 0.70 (0.59-0.82) < 0.001
      CDCS
      0 Reference Reference
      1 1.13 (0.95-1.34) 0.15
      2 1.58 (1.26-1.98) < 0.001
      Surgery
      Sub-lobar Reference Reference
      Lobectomy 0.72 (0.53-0.97) 0.03
      Pneumonectomy 0.97 (0.68-1.39) 0.87
      Stage
      IB Reference Reference
      II 1.29 (1.04-1.59) 0.02
      IIIA 2.28 (1.81-2.87) < 0.001
      LoS
      ≤ 6 days Reference Reference
      > 6 days 1.24 (1.06-1.46) 0.008
      30-day readmission
      No Reference Reference
      Yes 1.54 (1.20-1.99) 0.001


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    P1.07 - Poster Session with Presenters Present (ID 459)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      P1.07-035 - Circulating Cell-Free Tumor DNA (cfDNA) Testing in Small Cell Lung Cancer (ID 6193)

      14:30 - 14:30  |  Author(s): S.N. Waqar

      • Abstract

      Background:
      The diagnosis of small cell lung cancer (SCLC) is often made using fine needle aspiration or small biopsy of tumor specimens that are typically insufficient for next generation sequencing (NGS) analysis. Guardant360 (G360), a blood-based liquid biopsy that analyzes circulating free tumor DNA, may allow the detection of potentially targetable gene abnormalities without the need for repeated tissue biopsies.

      Methods:
      Peripheral blood samples from patients with SCLC were collected in two 10 mL tubes. Cell-free DNA was extracted and analyzed by digital sequencing for the detection of single nucleotide variants (SNVs), small Insertions and Deletions (INDELs), Copy Number Alterations (CNAs), and gene fusions. The Tumor Alterations Relevant for Genomics-Driven Therapy (TARGET) curated database (http://www.broadinstitute.org/cancer/cga/target) was queried for potentially actionable alterations.

      Results:
      240 samples from 227 de-identified patients were collected between June 2014 and June 2016. 7 patients had more than one sample analyzed. During this time period, the number of genes in the panel increased from 54 (10 samples) to 68 (87 samples) and finally to 70 (143 samples). The median time from sample collection to reporting was 13 days (range 8-28 days). Alterations in at least one gene were found in 222 (92.5%) of samples and 210 (92.5%) patients. SNVs in TP53 and RB1 were seen in 72.4% (152/210) and 25.7% (35/136) of patients with detectable alterations respectively. The most common potentially actionable alterations were amplifications of FGFR1 (11.8%) and ERBB2 (7.1%). MYC amplification, which was not considered an actionable alteration by TARGET but has been associated with sensitivity to Aurora kinase inhibitors in pre-clinical studies, was observed in 15.8% of patients. Eight patients had EGFR activating mutations (exon 21 L858R mutation or exon 19 deletion), of which 2 patients also had EGFR T790M mutation, likely representing transformation from NSCLC following targeted therapy with EGFR Tyrosine kinase inhibitors. KIF5B-ALK and AFAP1-RET fusions were seen in 1 patient each.

      Conclusion:
      G360 is a rapid non-invasive NGS platform which may be particularly useful in patients with advanced stage SCLC where tissue samples may be suboptimal for NGS. Due to the limited treatment options in this patient population, the detection of potentially actionable genes through G360 may provide valuable information to guide treatment decisions.

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    P2.03a - Poster Session with Presenters Present (ID 464)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P2.03a-014 - A Dose-Finding and Phase 2 Study of Ruxolitinib plus Pemetrexed/Cisplatin for Nonsquamous Non–Small Cell Lung Cancer (NSCLC) (ID 3874)

      14:30 - 14:30  |  Author(s): S.N. Waqar

      • Abstract

      Background:
      Dysregulation of the JAK/STAT pathway contributes to abnormal inflammatory responses, oncogenesis, treatment resistance, and poor prognosis in NSCLC. This phase 2 clinical trial evaluated the JAK1/JAK2 inhibitor ruxolitinib+pemetrexed/cisplatin as first-line treatment for patients with stage IIIB/IV or recurrent nonsquamous NSCLC and systemic inflammation (per modified Glasgow Prognostic Score [mGPS]).

      Methods:
      Key inclusion criteria were mGPS of 1/2 and ECOG performance status ≤1. Part 1, an open-label, 21-day safety run-in, assessed ruxolitinib (15 mg BID [chosen dose for Part 2]) plus pemetrexed (500 mg/m[2] IV on Day 1) and cisplatin (75 mg/m[2] IV on Day 1). Ruxolitinib dose selection for Part 2 required <3 dose-limiting toxicities (DLTs) for 9 evaluable patients. Part 2 randomized patients to ruxolitinib+pemetrexed/cisplatin or placebo+pemetrexed/cisplatin. The trial was terminated early for lack of efficacy in other solid tumor programs in patients with high systemic inflammation.

      Results:
      All 15 patients enrolled in Part 1 received ruxolitinib 15 mg BID plus pemetrexed/cisplatin. Median age was 64 years; male, 80%; mGPS 1, 80%. Median treatment duration was 140 days. The Table reports Part 1 safety data. Four patients were inevaluable for DLTs (<80% compliance, n=2; disease progression, n=2). No DLTs occurred in 11 evaluable patients. The Part 1 overall response rate (ORR) was 53% (8/15; all partial responses). At study termination, 39 and 37 patients were randomized in Part 2 to ruxolitinib and placebo, respectively. Median treatment duration was 43 days. ORR was 31% (12/39) with ruxolitinib+pemetrexed/cisplatin versus 35% (13/37) with placebo+pemetrexed/cisplatin (all partial responses). The short follow-up duration may limit interpretation of Part 2 efficacy. The Part 2 safety profile was consistent with Part 1 (data to be presented).

      Table. The Most Common Treatment-Emergent Adverse Events in Part 1
      Ruxolitinib+Pemetrexed/Cisplatin (N=15)
      Event, n (%) All-Grade Grade 3/4
      Nonhematologic*
      Nausea 11(73) 1(7)
      Fatigue 8(53) 3(20)
      Vomiting 8(53) 1(7)
      Constipation 7(47) 0
      Diarrhea 7(47) 0
      Dizziness 7(47) 0
      Peripheral edema 7(47) 0
      Decreased appetite 6(40) 0
      Pyrexia 6(40) 0
      Dyspnea 5(33) 1(7)
      Pneumonia 4(27) 3(20)
      Pulmonary embolism 2(13) 2(13)
      Sepsis 2(13) 2(13)
      New/worsening hematologic laboratory abnormalities
      Anemia 13(87) 5(33)
      Lymphopenia 11(73) 2(13)
      Leukopenia 9(60) 1(7)
      Neutropenia 9(60) 5(33)
      Thrombocytopenia 9(60) 1(7)
      *Common all-grade (≥30%) or grade 3/4 (≥10%) events.

      Conclusion:
      Ruxolitinib 15 mg BID had an acceptable safety profile in combination with pemetrexed/cisplatin as first-line treatment of patients with stage IIIB/IV or recurrent nonsquamous NSCLC.