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S.N. Gettinger



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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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      MO07.06 - Updated results of a first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies (ID 2400)

      16:45 - 16:50  |  Author(s): S.N. Gettinger

      • Abstract
      • Presentation
      • Slides

      Background
      AP26113 is a novel tyrosine kinase inhibitor (TKI) that exhibits pan-ALK inhibitory activity against all 9 clinically-identified crizotinib-resistant mutants, including the L1196M gatekeeper, in preclinical experiments. AP26113 also inhibits ROS1 and selectively inhibits mutant EGFR (EGFRm) in preclinical experiments, including the T790M resistance mutation, without affecting the native receptor.

      Methods
      We report data from the dose finding component (3+3 design) of a phase 1/2 open-label, multicenter study in patients with advanced malignancies (except leukemia) refractory to available therapies or for whom no standard treatment exists. Dosing was once daily (QD) or twice daily.

      Results
      As of 17 April 2013, 55 patients were enrolled: 30mg (daily dose) n=3, 60mg n=3, 90mg n=8, 120 mg n=15, 180mg n=15, 240mg n=9, 300mg n=2; 62% female, median age 58 yrs; diagnoses: non-small cell lung cancer (NSCLC, n=47), other (n=8). 33 patients discontinued: 22 disease progression, 6 adverse event (AE), 4 deaths (2 possibly related: sudden death, hypoxia), 1 withdrawal by subject. The most common AEs included fatigue (40%), nausea (36%), and diarrhea (33%), which were generally grade 1/2 in severity. The most common grade 3/4 AE was pneumonia (5%). Two patients experienced dose limiting toxicities: grade 3 ALT increase in 1 patient (240mg QD); grade 4 dyspnea and grade 3 hypoxia in 1 patient (300mg QD). Twenty-eight patients had ALK+ history (24 NSCLC, 4 other). Among 24 evaluable ALK+ patients, 15 responded. Responses were observed in 2/4 (50%) ALK+ TKI-naïve patients and 13/17 (76%) ALK+ patients with prior crizotinib therapy and no other ALK inhibitor exposure. Among ALK+ NSCLC patients with prior crizotinib only, 12/16 (75%) responded. The longest response is 40+ weeks (ongoing). 4 of 5 ALK+ patients with untreated or progressing CNS lesions at baseline and with follow-up scans had evidence of radiographic improvement in CNS, including 1 patient resistant to crizotinib and LDK378 (overall response = stable disease). CNS lesion improvements in all 4 patients are ongoing, with durations ranging from 15+ to 28+ weeks. Twenty patients had EGFRm history (19 NSCLC, 1 SCLC); 18 had ≥1 prior EGFR TKI. Of 18 evaluable EGFRm patients, 1 patient (prior erlotinib) responded at 120mg QD (duration 26+ weeks, ongoing), 7 patients had stable disease, including 4 with T790M by history (1 ongoing at 240mg QD, duration 16+ weeks). The maximum tolerated dose has not been defined; however, based on safety, efficacy, and pharmacokinetics, the recommended phase 2 dose (RP2D) is 180mg QD. Updated data will be presented.

      Conclusion
      AP26113 has promising anti-tumor activity in patients with ALK+ NSCLC and other ALK+ tumors, with initial evidence of activity in EGFRm patients, and is generally well tolerated. Five phase 2 cohorts are enrolling at the RP2D (180mg QD): 1) ALK inhibitor-naïve ALK+ NSCLC, 2) crizotinib-resistant ALK+ NSCLC, 3) single EGFR TKI-resistant NSCLC with documented T790M, 4) other tumors with AP26113 targets, 5) crizotinib-naïve or –resistant ALK+ NSCLC with active CNS metastases. Further phase 1 testing at 240mg QD will occur in EGFRm patients with documented T790M. NCT01449461

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    MO16 - Prognostic and Predictive Biomarkers IV (ID 97)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO16.04 - Analysis of HER2 amplification in non-small cell lung cancers (NSCLCs) with acquired resistance (AR) to Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) (ID 2951)

      16:30 - 16:35  |  Author(s): S.N. Gettinger

      • Abstract
      • Presentation
      • Slides

      Background
      Recent studies have demonstrated the feasibility of rebiopsy in patients (pts) with EGFR mutant NSCLC at the time of AR to the EGFR tyrosine kinase inhibitors (TKIs) erlotinib or gefitinib, and provide estimates of the prevalence of well described mechanisms of AR including the EGFR T790M mutation, MET amplification and small cell lung cancer (SCLC) transformation. HER2 amplification has also been described in cases of AR to EGFR TKIs, however, its exact frequency is still unclear. Moreover, comprehensive analysis of paired pre- and post-treatment samples to establish whether HER2 amplification is acquired during treatment with TKIs have not been performed. This prompted us to further investigate HER2 amplification in EGFR mutant NSCLC cases.

      Methods
      Pts with metastatic or recurrent NSCLC who developed AR while on a molecularly targeted agent were enrolled on an IRB approved repeat biopsy protocol. Tumor biopsies were obtained at the time of AR, and histopathological and molecular analyses of the tumors were performed. Known mechanisms of AR to EGFR TKIs were analyzed (T790M mutation, MET amplification and SCLC transformation) as well as amplification of HER2. The presence of T790M was assessed either by Taqman or pyro-sequencing (unless T790M status was available from an outside institution). HER2 and MET amplification were determined using fluorescence in situ hybridization (FISH).

      Results
      41 pts with AR to EGFR TKIs (erlotinib or gefitinib) were enrolled at YCC between Jan 2012 and May 2013. Histological analysis of all specimens revealed transformation of adenocarcinoma to SCLC in 3 cases (7%). Depending on the availability of tissue, samples were prioritized for T790M analysis followed by MET and HER2 amplification. T790M was identified in 36% of pts; MET and HER2 amplification were found in 11% and 10% of samples respectively. In the two cases with HER2 amplification, analysis of the pre-treatment specimen revealed that amplification of this receptor tyrosine kinase preceded treatment with EGFR-TKIs, however, the amplification level was lower pre-treatment in both cases. Specifically the ratio of HER2 to CEP17 probes was 2.8 pre-treatment in both cases and increased to 4.3 and 8 following TKI treatment. HER2 amplification was mutually exclusive with the other tested mechanisms of resistance.

      Conclusion
      T790M was the most commonly identified mechanism of AR to EGFR TKIs in the YCC cohort consistent with other studies. MET amplification, HER2 amplification and SCLC transformation were also observed. The observation that HER2 was amplified pre-treatment warrants further investigation of HER2 amplification in AR and pre-treatment specimens. Whole exome sequencing of specimens without known resistance mechanisms is ongoing.

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    MO18 - NSCLC - Targeted Therapies IV (ID 116)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 3
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      MO18.01 - An analysis of the relationship of clinical activity to baseline EGFR status, PD-L1 expression and prior treatment history in patients with non-small cell lung cancer (NSCLC) following PD-L1 blockade with MPDL3280A (anti-PDL1) (ID 2347)

      16:15 - 16:20  |  Author(s): S.N. Gettinger

      • Abstract
      • Presentation
      • Slides

      Background
      NSCLC may utilize PD-L1 overexpression to escape immune surveillance. This mechanism has been suggested by recent clinical studies showing that NSCLC can respond to PD-L1/PD-1 blockade. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, aims to restore tumor-specific T-cell immunity by blocking PD-L1 from binding to its receptors, PD-1 and B7.1.

      Methods
      Patients received MPDL3280A IV q3w for up to 1 year in a Phase I dose escalation/expansion study. Objective response rate (ORR) was assessed by RECIST v1.1 and included unconfirmed/confirmed responses. EGFR and KRAS status was initially assessed locally by investigators. Archival tissue was analyzed centrally for PD-L1 expression by IHC.

      Results
      As of Feb 1, 2013, 52 NSCLC patients were evaluable for safety and treated at doses of 0.03-20 mg/kg. The median age of patients was 61 years (range, 24-83). 17 (33%) of patients were ECOG PS 0 and 35 (67%) of patients were ECOG PS 1. Prior treatments included surgery (89%), radiotherapy (54%) and systemic therapy (98%). 15% of patients received 1 prior regimen, 21% received 2 and 62% received ≥3. Additionally, 14%, 62% and 25% of patients were EGFR-mutation positive, EGFR WT and EGFR status unknown/undetermined, respectively, and 12%, 40% and 48% of patients were KRAS-mutation positive, KRAS WT and KRAS status unknown/undetermined, respectively. Patients received treatment with MPDL3280A for a median duration of 106 days (range 1-450). Treatment-related Gr3/4 AEs occurred in 12% of patients, including fatigue (4%) and hypoxia (4%). 1 patient experienced a Gr3/4 immune-related AE (Gr3 hyperglycemia). No Gr3-5 pneumonitis or diarrhea was reported. 41 NSCLC patients first dosed at 1-20 mg/kg prior to Aug 1, 2012, were evaluable for efficacy. An ORR of 22% (9/41) was observed in patients (squamous [n=9]/nonsquamous [n=31]) with a duration of response range of 1+ to 214+ days. Additional patients had nonconventional responses after apparent radiographic progression but were considered to have progressive disease in this analysis. All responses were ongoing or improving at data cutoff. The 24-week PFS was 46%. ORR by patient characteristics was also examined. The ORR for patients with ≤2 prior therapies was 23% (4/17) and 23% (5/22) for patients with >2 prior therapies. Additionally, the response for former/current smokers was 23% (8/35) versus 17% (1/6) for never smokers. Between EGFR-mutation positive and EGFR WT patients, the ORRs also did not differ (25% [1/4] and 19% [5/26], respectively). In contrast, PD-L1 status was associated with ORR response as patients with PD-L1–positive tumors had an ORR of 80% (4/5) and patients with PD-L1–negative tumors had an ORR of 14% (4/28). Updated data, including responses by KRAS status, will be presented.

      Conclusion
      Treatment with MPDL3280A was generally well tolerated, with no cases of Gr3-5 pneumonitis. Rapid and durable responses were observed, including in an EGFR-mutation positive patient. Responses to MPDL3280A did not appear influenced by the number of prior treatment regimens but did appear to be associated with PD-L1 tumor status. Additional studies have been initiated in NSCLC.

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      MO18.03 - Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with non-small cell lung cancer (NSCLC): overall survival and long-term safety in a phase 1 trial (ID 2356)

      16:25 - 16:30  |  Author(s): S.N. Gettinger

      • Abstract
      • Presentation
      • Slides

      Background
      Blockade of programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, can overcome immune resistance and mediate tumor regression (Topalian S, et al. New Engl J Med. 2012;366:2443-54). We present long-term safety and efficacy outcomes from a phase 1 study of nivolumab, a fully human IgG4 PD-1 receptor blocking monoclonal antibody, in patients with advanced NSCLC.

      Methods
      NSCLC patients enrolled between 2008–2012 received nivolumab 1, 3, and 10 mg/kg IV Q2W on either dose escalation or subsequent expansion cohorts. Tumors were assessed (RECIST 1.0) after each 4-dose cycle. Protocol was amended (Jan. 23, 2012) to explore nivolumab’s potential to deliver prolonged overall survival (OS) for the initial and expansion cohorts and the overall population.

      Results
      129 pretreated NSCLC patients (non-squamous [n=74], squamous [n=54], unknown histology [n=1]) were treated as of March 2013. Responses (CR/PR) occurred in 22 patients (17%) and were durable (estimated median response duration, 74.0 weeks [6.1+, 133.9+]), and ongoing in 55% (12/22) of patients. The highest objective response rate (ORR) was at 3 mg/kg (24%) across NSCLC histologies. Responses were rapid; 50% of patients (11/22) demonstrated response at first tumor assessment (8 weeks). Among 12 responders who discontinued therapy for reasons other than disease progression, 3 responded for ≥24 weeks post therapy discontinuation, and all 3 had not progressed at the time of this analysis. An additional 6 of the 122 patients (5%) demonstrated unconventional “immune-related” responses (based on target lesions), but were not included among responders. Survival benefit was demonstrated by 1-year and 2-year landmark OS rates (42% and 14%; Table). Median OS was 9.6 months across doses and 14.9 months at 3 mg/kg across histologies. Median OS across doses was similar for squamous/non-squamous patients. Any grade drug-related select adverse events (AEs) occurred in 41% (53/129) of patients (grade 3/4 select AEs, 5% [6/129]); most common being skin (16%), gastrointestinal (12%), and pulmonary (7%). Any grade drug-related pneumonitis occurred in 6% (8/129) of patients (grade 3/4 pneumonitis, 2% [3/129]), resulting in 2 deaths early in the trial, leading to increased emphasis on management algorithms. Characteristics and management of nivolumab-related pneumonitis will be summarized.

      Cohort Dose, mg/kg ORR[a] no. of patients/total no. of patients (%) [95% CI] Estimated median response duration, wk (range) Median OS,[b] mo (95% CI) OS rate, % (95% CI); patients at risk, n
      1 y 2 y
      NSCLC (n=129)[c] All doses 22/129 (17.1) [11.0, 24.7] 74.0 (6.1+, 133.9+) 9.6 (7.8, 12.4) 42 (33, 51); 43 14 (4, 24); 5
      1 1/33 (3.0) [0.1, 15.8] 63.9 (63.9, 63.9) 9.2 (5.6, 11.1)
      3 9/37 (24.3) [11.8, 41.2] NR (16.1+, 133.9+) 14.9 (9.5, NE)
      10 12/59 (20.3) [11.0, 32.8] 83.1 (6.1+, 117.1+) 9.2 (5.2, 12.4)
      Initial cohort (n=19) All doses 9.6 (4.5, 19.8) 42 (20, 64); 8 26 (7, 46); 5
      Expansion cohort (n=110) All doses 9.9 (7.8, 12.5) 42 (32, 51); 35
      Squamous (n=54) All doses 9/54 (16.7) [7.9, 29.3] NR (16.1, 133.9+) 9.2 (7.3, 12.5) 39 (25, 53); 16
      1 0/15 0 8.0 (2.6, 13.3)
      3 4/18 (22.2) [6.4, 47.6] NR (16.1, 133.9+) 9.5 (6.7, NE)
      10 5/21 (23.8) [8.2, 47.2] 83.1 (16.1, 117+) 10.5 (7.8, 12.5)
      Non-squamous (n=74) All doses 13/74 (17.6) [9.7, 28.2] 63.9 (6.1+, 74.0+) 10.1 (7.2, 13.7) 43 (31, 54); 26
      1 1/18 (5.6) [0.1, 27.3] 63.9 (63.9, 63.9) 9.9 (5.6, 22.7)
      3 5/19 (26.3) [9.1, 51.2] 74.0 (24.3, 74.0+) 18.2 (10.3, 18.2)
      10 7/37 (18.9) [8.0, 35.2] NR (6.1+, 65.7+) 7.4 (4.6, 12.4)
      [a]ORR = ([CR + PR] ÷ n) × 100.[b]OS estimates after 1 year reflect censoring and shorter follow-up for patients enrolling later in the study.[c]Non-squamous (n=74), squamous (n=54), and unknown histology (n=1) NE = not estimable; NR = not reached.

      Conclusion
      In advanced NSCLC patients, nivolumab produced durable responses and survival benefit (1-year OS rate, 42%), with a long-term safety profile acceptable for the outpatient setting, supporting ongoing development in phase 3 trials with survival endpoints. Additional follow-up on patient survival will be presented at the time of the meeting.

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      MO18.06 - BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 1949)

      16:45 - 16:50  |  Author(s): S.N. Gettinger

      • Abstract
      • Presentation
      • Slides

      Background
      Effective therapeutic strategies for mutant KRAS and other biomarkers of resistance in refractory NSCLC remain an unmet medical need, while a personalized medicine approach is increasingly adopted in NSCLC guided by tumor molecular profiling. The BATTLE-2 clinical study is using EGFR, PI3K/AKT and MEK inhibitors and is designed to identify biomarkers for optimal patient selection for these therapies (ClinicalTrials.gov NCT01248247).

      Methods
      This is a four-arm, open-label, multi-center, biopsy-driven, adaptive randomization, phase II clinical trial in NSCLC pts that failed at least 1 prior line of therapy. Patients are adaptively randomized to 4 arms: erlotinib, erlotinib plus the AKT inhibitor MK-2206, MK-2206 plus the MEK inhibitor selumetinib, and sorafenib. The primary objective is 8-week disease control rate (DCR). The trial is conducted in 2 stages. In Stage 1, 200 evaluable pts are adaptively randomized (AR) based on observed 8-week DCR and KRAS mutation status while predictive biomarkers are being developed by means of gene expression profiling, targeted next generation sequencing and protein expression. EGFR sensitizing mutations and EML4/ALK translocation in pts that are erlotinib and crizotinib naïve are exclusion criteria, while erlotinib resistant patients are excluded from erlotinib monotherapy. In Stage 2, the AR model is refined to include the most predictive biomarkers tested in Stage 1, with subsequent Stage 2 AR based on the new algorithm, to a total of 400 evaluable pts. Selection of Stage 2 single and/or composite markers follows a rigorous, internally and externally reviewed statistical analysis that follows a training, testing methodology with validation in stage 2 of the trial. All Stage 1 and 2 randomization biomarker assays are CLIA-certified.

      Results
      286 pts have been enrolled, 236 biopsies performed,172 pts randomized, and 167 pts treated. 144 pts are evaluable for the 8-week DCR endpoint. Within the randomized pts group KRAS mutation rate is 22.8%, and EGFR mutation rate 14.8%, while 36.3% patients have been previously treated with erlotinib. Treatment is well tolerated with no unanticipated toxicity.

      Conclusion
      Accrual updates, demographics, and further details will be presented at the meeting. (Supported by NCI R01CA155196-01A1)

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    MO19 - Lung Cancer Immunobiology (ID 91)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO19.09 - Molecular correlates of PD-L1 status and predictive biomarkers in patients with non-small cell lung cancer (NSCLC) treated with the anti-PDL1 antibody MPDL3280A (ID 1653)

      11:20 - 11:25  |  Author(s): S.N. Gettinger

      • Abstract
      • Presentation
      • Slides

      Background
      In NSCLC, antitumor immune response may be inhibited by PD-L1 expression. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, aims to restore tumor-specific T-cell immunity by blocking PD-L1 binding to its receptors, PD-1 and B7.1.

      Methods
      Patients with squamous or nonsquamous NSCLC received MPDL3280A IV q3w up to 1 year as part of a phase I dose escalation/expansion study. Objective response rate (ORR) was assessed by RECIST v1.1 and included unconfirmed/confirmed responses. EGFR and KRAS status was initially assessed locally by investigators. Archival tumor tissues were evaluated centrally by IHC for PD-L1 and CD8. A qPCR-based gene expression panel measuring ≈90 immune-related genes was used to characterize the tumor immune microenvironment at baseline and during MPDL3280A treatment.

      Results
      41 NSCLC patients first dosed at 1-20 mg/kg prior to Aug 1, 2012, were evaluable for efficacy with an ORR of 22%. Baseline tumor samples were available for IHC (n=33) and for gene expression analysis (n=29). Of patients with available tissue, 5 were PD-L1 tumor status positive and 28 were PD-L1 tumor status negative. Relationship between PD-L1 status and EGFR/KRAS status is described below (table). Elevated baseline PD-L1 expression was associated with response to MPDL3280A (80% ORR vs 14% ORR for PD-L1negative patients), and PD-L1 expression coordinated with CD8+ T cells. A Th1-type T-cell gene signature (including CD8, Granzyme-B and EOMES) was associated with treatment response. Non-responders exhibited at least a 2-fold higher ratio over CD8 of genes associated with immunosuppression, including RORC, FOXP3, TGFb1 and IL10 compared with responders. On treatment, responding tumors across indications showed increasing PD-L1 expression and a Th1-dominant immune infiltrate, providing evidence for adaptive PD-L1 up-regulation.

      Conclusion
      PD-L1 expression and a Th1 driven T-cell gene signature correlated with response to MPDL3280A in NSCLC, and MPDL3280A therapy led to T-cell reactivation and restored antitumor immunity. Additionally, expression of immune suppressive factors in NSCLC tumors is associated with a lack of benefit from MPDL3280A. These data provide mechanistic insights into immunotherapy and patient selection for MPDL3280A monotherapy. Preliminary observations suggest clinical activity and molecular characteristics may be associated with PD-L1 tumor expression. Updated data will be presented. Table: Relationship between PD-L1 status and EGFR/KRAS mutational status

      PD-L1-Positive (n = 5) PD-L1-Negative (n = 28) PD-L1 Unknown (n = 7) Overall (n = 40)*
      EGFRm, n 1 2 1 4
      EGFR WT, n 2 20 4 26
      EGFR Unknown, n 2 6 2 10
      KRASm, n 1 4 1 6
      KRAS WT, n 2 8 3 13
      KRAS Unknown, n 2 16 3 21
      * 1 patient had missing data.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-003 - Correlative Analysis of Circulating Biomarkers from a Phase 1b/2 trial of Cabozantinib (C) with or without Erlotinib (E) in Patients (Pts) with Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) (ID 266)

      09:30 - 09:30  |  Author(s): S.N. Gettinger

      • Abstract

      Background
      Cabozantinib (C) is a potent ATP-competitive inhibitor of MET and vascular endothelial growth factor receptor 2 (VEGFR2) along with KIT, RET, AXL, TIE2, and FLT3. Hepatocyte growth factor (HGF), the ligand of MET, and VEGF act synergistically to promote angiogenesis. There are currently no widely accepted prognostic or predictive biomarkers for anti-angiogenic agents.

      Methods
      This is a retrospective correlative biomarker study from the phase 1b/2 trial of C+/-E in stage IIIB-IV NSCLC. All pts had to fail prior therapy with E. Both drugs are oral and dosed daily. C dosing is in the free-base equivalent weight. In phase I, there was a 2 week lead in with E and the cohorts included: 1A (60 mg C+150 mg E), 2A (60 mg C+100 mg E), 3A (100 mg C+100 mg E), 4A (100 mg C+50 mg E), and 2B (40 mg C+150 mg E). In phase II, both drugs started simultaneously: Arm A (100 mg C) and Arm B (100 mg C+50 mg E). Pts were included in the study if a pre-E+C and post-C > day 29 plasma sample was available. The Milliplex 13-plex and Luminex 51-plex assays were used. For this preliminary analysis, select markers previously implicated in angiogenesis (bFGF, VEGF, sVEGFR1-3, IL-6, IL-8, IL-12, IL-17, PDGF-BB, ICAM-1, VCAM-1) and those of interest (ligands of KIT and MET- SCF and HGF, respectively) were analyzed. Log transformed mean fluorescence intensity (MFI) values and Wilcoxon Rank paired sum tests were used to detect changes from day 1-29. A change from baseline was noted to be significant if at least 15% (median) with α<0.05 (2-sided) and a trend if 10-15% (median) with α<0.08 (2-sided).

      Results
      73 pts included: 52 phase I and 21 phase II; median age 60 years; 23M/50F; 56.2% nonsmoker; 91.8% adenocarcinomas. The pts with samples from both time points were divided into two groups due to limited sample size and included: Group R (complete/partial response and stable disease> 6 months; n=22) and Group NR (stable disease< 6 months and progressive disease; n=51). The only marker that changed in a single direction in all subjects within a group was sVEGFR2 in group R. Overall, significant decreases were noted in sVEGFR1-3, IL-6, PDGF-BB, and trended in IL12p70 and IL-17. By subgroups: Group R had significant decreases in bFGF, VEGF, sVEGFR1-3, IL-6, IL-8, IL-12(p40+p70), IL-17, PDGF-BB, SCF, and trended in HGF (median 10.1% ↓, p=0.0275); and Group NR had significant decreases in sVEGFR2-3, IL-6, PDGF-BB, and trended in sVEGFR-1, IL-6, and IL-17.

      Conclusion
      Both groups R+NR had a decrease in sVEGFR-2, suggesting that this is a marker of treatment with C rather than a marker of response. However, overall group R had larger dynamic decreases of immune markers than group NR. HGF, which is targeted downstream by C and plays a role in angiogenesis and E resistance, had a trend to decrease in group R but not group NR. This study is retrospective with a small sample size, imbalanced numbers per response subgroup, and is exploratory in nature.