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A.A. Chiappori



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    MO05 - Prognostic and Predictive Biomarkers II (ID 95)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO05.03 - A gene expression platform to predict benefit from adjuvant external beam radiation in resected non-small cell lung cancer. (ID 268)

      16:25 - 16:30  |  Author(s): A.A. Chiappori

      • Abstract
      • Presentation
      • Slides

      Background
      To date, no personalized decision-making tool exists for adjuvant radiation after resection of non-small cell lung cancer (NSCLC). Our objective was to retrospectively determine if our previously developed 10-gene expression signature, called radiosensitivity index (RSI), would classify patients into radioresistant (RSI-poor) or radiosensitive (RSI-good) using disease-free survival (DFS).

      Methods
      Inclusion criteria: pathologic AJCC v6 stage III NSCLC at time of resection, negative margins, at a single institution between 2000 and 2012. Neo or adjuvant chemotherapy was required. For radiation group (RT), at least 45 Gy of conformal or intensity-modulated radiation was required. An identical stage group (control) did not receive radiation. Gene expression profiling was conducted on primary lung tumor mRNA. DFS was defined as time-to-recurrence or death from any cause. Predefined cut-point was lowest quartile of calculated RSI. Two-sided log-rank and Cox regression were used.

      Results
      Of 144 screened, 95 were eligible (53 RT and 42 control). Demographics: median age 67 yrs, 54% female, 96% white, and 91% current / former smokers. Operations consisted of 56% lobectomy, 26% pneumonectomy, and 18% segmentectomy/wedge. Adjuvant doublet consisted of 48% taxane, 32% gemcitabine, or 20% other. Mean RT dose 54.8 Gy, median follow-up 3.5 yrs. Histology: 64% adenoca, 25% squamous, 10% large-cell. Mean tumor volume 58 cm[3], 77% were pN2, 58% had angiolymphatic invasion and 51% were poorly-differentiated. Mean preoperative PET SUV~max~ was 9.5. No imbalance in clinical factors were observed between RSI-good vs. RSI-poor. On univariate analysis, for RT group, median DFS for RSI-good vs RSI-poor was 5.8 yrs vs. 1.4 yrs, HR 4.2 (95% CI 1.9 – 9.5), p = 0.017. 5-year DFS was 63% vs 22%, p = 0.01. No significant difference was observed for the chemo-only control group, with median DFS for RSI-good vs. RSI-poor: 2.3 vs 2.7 yrs, HR 0.7 (95% CI 0.3 – 1.6), p = 0.98. A test for interaction confirmed that the effect was restricted to the RT group and not the control, with p = 0.04. On multivariate analysis, for the RT group, the RSI was more strongly associated with DFS than any other variable (age, gender, tumor volume, nodal status, baseline SUV~max~, histology, grade, LVI, and operation). After inclusion of covariates, it remained an independent predictive variable with HR 3.8 (95% CI 1.6 – 9.2) p = 0.003. Figure 1

      Conclusion
      RSI appears to be predictive for benefit from adjuvant radiation. Additional independent prospective validation is required.

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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)

      11:25 - 11:35  |  Author(s): A.A. Chiappori

      • 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)

      11:35 - 11:45  |  Author(s): A.A. Chiappori

      • 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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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-024 - A phase I/II randomized trial using GM-CSF-producing and CD40L-expressing bystander cell line (GM.CD40L) vaccine plus or minus CCL21 in stage IV lung adenocarcinoma: Updated results (ID 1878)

      09:30 - 09:30  |  Author(s): A.A. Chiappori

      • Abstract

      Background
      Background: The GM.CD40L vaccine, an allogeneic tumor cell-based vaccine generated from a human bystander cell line which secretes GM-CSF and expresses CD40L on the surface (GM.CD40L), was developed by our team. It serves to recruit and activate dendritic cells. The mature dendritic cells in turn travel to regional lymph nodes and help to activate T cells which result in systemic tumor cell killing. CCL21 is a chemokine which serves to enhance recruitment of T cells and enrich T cell responses. In NSCLC mouse model, the vaccine combination of GM.CD40L plus CCL21 demonstrated additive effects.

      Methods
      Methods: We conducted a phase I/II randomized study to evaluate the GM.CD40L (Arm A) vs. GM.CD40L.CCL21 (Arm B) vaccine in patients with lung adenocarcinoma who had failed first-line therapy. Primary endpoints were safety and tolerability of Arm B in phase I and 6 month progression-free survival (PFS) in phase II; secondary endpoints included anti-tumor immune responses and T-cell responses by ELISpot assay on PBMC. Immune-related response criteria (irRC) determined discontinuation from study treatment at the discretion of the PI/treating physician. Intradermal vaccines were administered in the bilateral axilla and groin every 14 days for 3 doses and then monthly for 3 doses. A two-stage minimax design was used. Survival probabilities over time in each treatment group were estimated using the method of Kaplan and Meier.

      Results
      Results: Between 4/2012 and 4/2013, phase 1 enrolled 3 patients on GM.GD40L.CCL21, while Arm A enrolled 17 and Arm B enrolled 14 patients. The baseline characteristics, including those in phase I are as follows: median age: 66/68 years, females: 50%/50%, PS1: 64.7%/76.5%, median prior regimens: 2.5/3 for Arm A vs. Arm B, respectively. No DLT’s were observed during phase 1. The most common toxicities for Arm A vs. Arm B were injection site reaction (70.6%/70.6%), fatigue (29.4%/41.2%), anorexia (23.5%/29.4%), and pain in extremity (5.9%/5.9%). Median PFS for Arm A vs. B was 1.9 vs. 4.4 months (p=0.10). All patients who remained on study per MD discretion/irRC, did ultimately demonstrate further progression on subsequent imaging. Treatment was discontinued in all of those patients. In Arm A versus Arm B, stable disease was 4/8 and progressive disease was 8/8, respectively. The disease control rate (DCR) for Arm B compared with Arm A was 50% versus 33%, respectively. ELISpot assay for immune responses and flow cytometry studies on PBMCs are underway.

      Conclusion
      Conclusion: GM.CD40L plus CCL21 chemokine is well tolerated. The phase II trial including further immune response assays collected pre and post vaccine are underway and updated results will be presented.

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    P2.13 - Poster Session 2 - SCLC (ID 201)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.13-002 - Randomized Phase II Study of Single Agent OSI-906, an Oral, Small Molecule, Tyrosine Kinase Inhibitor (TKI) of the Insulin Growth Factor-1 Receptor (IGF-1R) Versus Topotecan for the Treatment of Patients with Relapsed Small Cell Lung Cancer (SCLC) (ID 920)

      09:30 - 09:30  |  Author(s): A.A. Chiappori

      • Abstract

      Background
      SCLC typically presents with advanced (extensive stage) disease. Despite an initial response to chemotherapy, they all relapse and rarely survive beyond 2 years. Treatment of relapsed SCLC is limited (topotecan) and dependent on the response to initial chemotherapy (sensitive vs. refractory relapse). Downstream activation of PI3K-AKT, through IGF-1R pathway signaling plays a role in both, growth/survival and resistance to chemotherapy in SCLC. Growth inhibition and chemosensitization with IGF-1R inhibitors correlates with the PI3K-AKT inhibitory signaling and suggests AKT activation as a potential biomarker. OSI-906, is a well tolerated oral, small molecule, potent inhibitor of IGF-1R

      Methods
      A phase II randomized study comparing the efficacy of OSI-906 vs topotecan in patients with rSCLC is currently being conducted. Primary endpoint is PFS, summarized with the K-M method. An increase in median PFS from 2.5 to 4.175 months (in the experimental arm B) is proposed. A total of 95 patients are planned. Biomarkers of IGF-1R inhibition are explored in plasma, PBMC and using Radiomics. Eligible patients must have proven rSCLC, platinum sensitive (sen) or resistant (res) disease, ECOG PS 0-2 and adequate hematologic, renal and hepatic function. Fasting glucose <160 mg/dl, QTc < 450 msec and measurable disease by RECIST v1.1 are required. Pregnant, breast-feeding, diabetic and cirrhotic patients as well as those taking insulin/insulinotropic agents are excluded. Patients are randomized (2:1) to the experimental arm (B): OSI-906, 150 mg PO BID, until progression or to the standard arm (A): topotecan, 1.5 mg/m[2] IV daily x5 OR 2.3 mg/m[2] PO daily x5, for 4 cycles. Crossover to OSI-906 is allowed.

      Results
      Figure 1 Thirty-three patients have been enrolled; A=10 (res=6, PS 2=2) and B=23 (res=15, PS 2=4). M/F= 13/20; ECOG PS 0/1/2 = 8/19/6. Platinum sen/res = 12/21. Two patients were not treated (A/B = 1/1). Adverse events are described in Table 1. No responses have been observed. Only 2/6 and 1/15 patients in arms A and B respectively achieved SD at 6 weeks. Median PFS (A/B) was 2.1 (95% CI; 0.6, 3.6) and 1.3 (95% CI; 1.0, 1.4) months respectively (p = 0.0149). OS was not reached in arm A and 2.7 (95% CI; 1.5, …) months in arm B (p = 0.1716).

      Conclusion
      OSI-906 is safe in rSCLC patients. In our unselected, high risk population, efficacy in both arms, but particularly in arm B appears suboptimal. The study continues to accrue to reach the sample size and follow up time needed for more robust conclusions.