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M.A. Socinski



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    MINI 09 - Drug Resistance (ID 107)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI09.06 - Oncogenic Drivers including RET and ROS1 plus PTEN Loss and MET by IHC in Patients with Lung Adenocarcinomas: Lung Cancer Mutation Consortium 2.0 (ID 2114)

      M.A. Socinski

      • Abstract
      • Presentation
      • Slides

      Background:
      The Lung Cancer Mutation Consortium (LCMC) 1.0 demonstrated multiplexed genomic platforms can assay 10 oncogenic drivers in tumor specimens from patients with lung adenocarcinomas. 28% of the patients with oncogenic drivers could be effectively targeted. The survival of these 275 patients treated with targeted agents was longer than the patients who were not treated with a targeted agent (Kris and Johnson JAMA 2014). The efficiency of Next-Generation Sequencing enables more comprehensive testing of additional aberrations with less tumor tissue. LCMC 2.0 was initiated to test tumor specimens for 12 oncogenic drivers and to provide the results to clinicians for treatment decisions and research purposes.

      Methods:
      The 16 site LCMC 2.0 is testing tumors from 1000 patients with lung adenocarcinomas in CLIA laboratories for mutations in KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, and NRAS, MET DNA amplification, and rearrangements in ALK as done in LCMC 1.0. The new genes that were added because of emerging information about potential therapeutic targets include MAP2K1 mutations, RET and ROS1 rearrangements, PTEN (MAb 138G4) loss and MET (MAb SP44) overexpression by immunohistochemistry (IHC). All patients were diagnosed with stage IIIB/IV lung adenocarcinoma after May 2012, had a performance status 0-2, and available tumor tissue.

      Results:
      Of 1073 patients registered, data is now reported for 759. The median age of the patients is 65 (23-90). The population includes 369 (55%) women; 164 (24%) never smokers, 399 (59%) former smokers, and 73 (11%) current smokers; 26 (4%) Asians, 58 (9%) African American, 548 (81%) Caucasian, and 43 (6%) of other races. As of April 2015 information on genomic and immunohistochemical changes for 675 eligible patients were recorded in our database. Alterations in oncogenic drivers were found in 45% of samples as follows: 159 KRAS (24%), 88 EGFR (13%), 25 ALK (4%), 19 BRAF (3%), 17 PIK3CA (3%), 9 HER2 (1%), 4 NRAS (1%) 0 AKT1, 28 had ≥ 2 findings (4%) and 25 MET DNA amplification (4%). The new genes studied in LCMC 2.0 revealed 1 MAP2K1 mutation (<1%), 19 RET (3%) and 9 ROS (1%) rearrangements, 94 had PTEN loss (14%), and 362 with MET overexpression (54%). As expected, PIK3CA mutations and PTEN loss by IHC were mutually exclusive in 109 of 111 (98%) patients’ tumors. Seventeen of the 23 (74%) with MET DNA amplification studied thus far with IHC had MET overexpression. Next-Generation platforms were used at 13 of 16 LCMC 2.0 sites.

      Conclusion:
      Next-Generation Sequencing is rapidly becoming routine practice at LCMC 2.0 centers with use going from 0 to 81% of sites since 2012. LCMC 2.0 identified additional targets (RET and ROS1 rearrangements and PTEN loss). PIK3CA and PTEN were largely mutually exclusive and an actionable oncogenic driver has been identified in the 45% of initial lung adenocarcinoma specimens. Supported by Free to Breathe

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    MINI 14 - Pre-Clinical Therapy (ID 119)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI14.08 - HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells and Inhibits Lung Cancer Stem Cells (ID 2789)

      M.A. Socinski

      • Abstract
      • Presentation
      • Slides

      Background:
      Ionizing radiation (IR) therapy is an integral component of treatment for NSCLC, however, the majority of patients succumb to this disease as the disease tends to relapse and metastasize. The failure of the therapies is associated with hypermalignant cancer-initiating cells (CICs). CICs are radiation-resistant; therefore, targeting CICs represent an important therapeutic strategy for improving the outcome of IR treatment. Ganetespib, a novel heat shock protein 90 (HSP90) inhibitor, reduces expression of multiple HSP90-dependent client oncoproteins. We evaluated both the in vitro and in vivo antitumor effects of ganetespib, in combination with IR, in human lung adenocarcinoma (AC) cells.

      Methods:
      The radiosentisizing activity of ganetespib, HSP90 inhibitor, was evaluated in human lung AC cells established from surgical tumor samples.

      Results:
      Ganetespib inhibits growth of bulk AC cells, as well as lung CICs, growing as tumor spheres. The cytotoxic effects of ganetespib G2/M cell cycle DNA repair, apoptosis, and senescence. All of these antitumor effects were both concentration- and time-dependent. At the molecular level, ganetespib inhibited pro-survival signaling in adenocarcinoma cells through decreased p-AKT expression, the downregulation of RAD51 and the upregulation of p21. Ganetespib, at low nanomolar concentrations sensitizes AC to IR treatment. Importantly, both pretreatment and post –radiation treatment (24h after IR) with ganetespib (3nM) could dramatically augment the antitumor effects of IR decreasing the survival rate of IR-treated cells. Our study suggests that ganetespib may impart radiosensitization through multiple mechanisms: such as the down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and the promotion of cellular senescence. In vivo, ganetespib was effective in reducing the tumor growth of primary T2821 tumor xenografts in mice and sensitized tumors to IR.

      Conclusion:
      The HSP90 inhibitor, ganetespib, potentiates the effect of IR in NSCLC and eliminates CICs. The radiosensitizing effect of ganetespib is mediated by the combinatorial inhibition of cell growth and survival pathways. Ganetespib is the most potent HSP90-mediated radiosensitizer yet reported in vitro, and for the first time validated in a clinically relevant in vivo model. The use of ganetespib as a therapeutic warrants a further investigation in the clinical setting.

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    MTE 02 - Patients, Investigators and Pharmaceuticals Working Together to Accelerate Research and Access: The Lung Cancer Master Protocol (Lung-MAP) Clinical Trial (Ticketed Session) (ID 54)

    • Event: WCLC 2015
    • Type: Meet the Expert (Ticketed Session)
    • Track: Advocacy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/07/2015, 07:00 AM - 08:00 AM, 105
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      MTE02.01 - Patients, Investigators and Pharmaceuticals Working Together to Accelerate Research and Access: The Lung Cancer Master Protocol (Lung-MAP) Clinical Trial (ID 1979)

      M.A. Socinski

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The traditional obstacles to approval of oncologic therapeutic agents, especially targeted therapies that address a rare-biomarker defined group of patients are the long processes from initial drug discovery to clinical implementation, the difficulties in recruitment for these clinical trials and high number of screen failures and the overall low rate of enrollment in clinical trials. The Lung Master Protocol (Lung-MAP, S1400) is a precedent-setting clinical trial designed to advance the efficient development of targeted therapies for squamous cell cancer of the lung (SCCA). There are few new effective therapeutic options for patients with advanced lung SCCA. Immunotherapies, including nivolumab, have already shown clear benefit for patients with SCCA in 2015 leading to approval by the FDA which has been an unprecedented step forward for the treatment of patients, however we are still lacking predictive markers for these therapies that are reliably selecting patients more likely to benefit. Lung-MAP (S1400) is aiming to identify biomarker-drug pairs that will lead to successful therapeutic outcomes and registration of new agents. It is a registration-intent master protocol that includes a screening component and clinical trial component; the clinical trial component includes multiple sub-studies which independently evaluate investigational therapies. The clinical trial component is designed to be modular such that new sub-studies can be added either as other sub-studies close or as new biomarker-drug pairs are identified for testing in this patient population. Lung-MAP is utlilizing a broad NGS screening platform capitalizing on the expanding application of genomic sequencing in oncology that has through the Cancer Genome Atlas and other sequencing initiatives revealed targetable genetic aberrations including gene mutations, rearrangements, amplifications, and deletions, and creating an immense opportunity to implement personalized therapy with a high potential to improve patients outcomes. Immunotherapy has been integrated in the design of Lung-MAP from its launch in June of 2014. The original study design and structure is shown in the figure. Figure 1 The modular design of the study has allowed for the flexibility to adapt to the approval of nivolumab and the hault in further development of AMG102 (rilotumumab) with discontinuation of the corresponding sub-study by implementing timely modifications which include the following:1)Eligibility has changed from exclusively second line therapy to second-or more line therapy 2)Pre-screening, while patient receive first line therapy has been added to boost accrual 3)the unmatched arm has been changed to a single (not randomized) arm study with the anti-PD-L1 agent MEDI-4736. Theses changes are reflected in the figure. Each independently conducted and analyzed sub-study specifies investigator-assessed progression-free survival (IA-PFS) and overall survival (OS) as the co-primary endpoints for the phase 3 primary objectives. The primary objectives for the phase 3 are to determine if there is a statistically significant difference in OS and to determine if there is both a clinically meaningful and statistically significant difference in IA-PFS. The conduct of Lung-MAP relies on close collaboration (a public-private partnership) among the NCI and NCTN (spearheaded by SWOG), the pharmaceutical industry, the Foundation for the NIH (FNIH), Friends of Cancer Research, advocates, and FDA. This Master Protocol will improve genomic screening of SCC patients for clinical trial entry, and improve time lines for drug-biomarker testing, allowing for inclusion of the maximum numbers of otherwise eligible patients. The clinical trial continues to be updated following science and alterations in the therapeutic landscape, with adaptations in design and incorporation of new agents against matched targets and the implementation of novel immunotherapy approaches for the unmatched arm. Figure 2





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    ORAL 32 - EGFR WT and MT Targeting (ID 144)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 2
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      ORAL32.03 - Efficacy and Safety of Necitumumab Continuation Therapy in Phase 3 SQUIRE Study (ID 1391)

      M.A. Socinski

      • Abstract
      • Presentation
      • Slides

      Background:
      The SQUIRE study demonstrated that the addition of necitumumab (N) to gemcitabine-cisplatin (GC) improved survival in patients with stage IV sq-NSCLC. This retrospective analysis compares efficacy and safety outcomes for patients who received single-agent N as continuation therapy after completion of chemotherapy treatment (CT) in GC+N arm to the continuation therapy-eligible population of the GC arm.

      Methods:
      Patients were randomized 1:1 to GC (G=1250 mg/m² iv, days 1 and 8; C=75 mg/m² iv, day 1) plus N (800 mg iv, days 1 and 8), or GC alone every 21 days up to 6 cycles. Patients in GC+N with no progression continued on N alone until progressive disease. In this analysis, we consider patients in GC+N arm who were alive and progression-free before the start of N single-agent therapy (GC+N arm continuation therapy patients) and patients in GC arm who were alive, progression-free after completion of CT and did not discontinue treatment due to adverse event (AE) (GC arm non-progressor patients). This analysis included patients in both arms who received ≥4 cycles of CT. Overall survival (OS) and progression-free survival (PFS) were measured from the date of randomization, with parameters estimated using the Kaplan-Meier method. Hazard ratios and 95% CIs between subgroups were estimated from stratified Cox proportional hazards models. OS and PFS for post-induction period were measured from the completion of CT + 21 days. Selected treatment-emergent AEs (TEAEs) for patients in each arm are presented in the table.

      Results:
      261 patients were progression-free, received ≥4 cycles of CT, and received ≥1 dose of N alone in GC+N arm. 215 pts in GC arm completed ≥4 cycles of CT, were progression-free, and did not discontinue due to AE. Patient baseline characteristics and exposure to CT were well balanced between GC+N and GC arms. Median OS from randomization in GC+N vs GC was 15.9 vs 15.0 months; HR 0.85 (95% CI, 0.69, 1.05). Median OS for post-induction period in GC+N vs GC was 11.5 vs 10.9 months; HR 0.84 (95% CI, 0.68; 1.04). Median PFS from randomization in GC+N vs GC was 7.4 vs 6.9 months; HR 0.86 (95% CI, 0.70, 1.06). Median PFS from post-induction period in GC+N vs GC was 3.2 vs 2.3 months; HR 0.85 (95% CI, 0.70, 1.04). Selected TEAEs (Overall):

      GC+N Continuation PatientsN = 261, % GC Non-ProgressorsN = 215, %
      Category Any Grade Grade ≥3 Any Grade Grade ≥3
      Neutropenia 55.9 34.1 57.7 33.0
      Anemia 46.7 10.0 49.3 8.8
      Thrombocytopenia 26.1 9.6 29.3 12.6
      Hypomagnesemia 42.1 14.9 18.6 0.9
      Conjunctivitis 11.9 0.8 3.3 0
      Rash 87.4 8.8 10.2 0.5
      Arterial thromboembolic event 5.7 3.1 0.5 0
      Venous thromboembolic event 9.2 3.8 4.2 0.9


      Conclusion:
      There was a consistent treatment effect in favor of GC+N continuation patients as compared to GC non-progressors with no unexpected increases in AEs.

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      ORAL32.05 - EGFR IHC and FISH Correlative Analyses (SQUIRE Trial): Necitumumab + Gemcitabine-Cisplatin vs Gemcitabine-Cisplatin in 1st-Line Squamous NSCLC (ID 2651)

      M.A. Socinski

      • Abstract
      • Presentation
      • Slides

      Background:
      SQUIRE, a randomized phase III study, demonstrated that the addition of necitumumab (N) (a second-generation, recombinant, human immunoglobulin G1 EGFR antibody) to gemcitabine-cisplatin (GC) improved overall survival (OS) in patients with stage IV squamous non-small cell lung cancer (NSCLC). Analyses of the relationship between efficacy and epidermal growth factor receptor (EGFR) protein expression using the immunohistochemistry (IHC) H-score=200 cut-point were previously reported (Thatcher et al. Lancet Onc, 2015; doi: 10.1016/S1470-2045(15)00021-2). Here we report additional exploratory analyses of the relationship with EGFR protein, as well as analyses of EGFR gene copy number.

      Methods:
      SQUIRE included mandatory tissue collection from archived tumor. EGFR protein expression was assessed by IHC in a central lab, using the Dako EGFR PharmDx kit. Analyses of the relationships between efficacy outcomes with EGFR across the range of protein levels were performed, using methodologies including subpopulation treatment effect pattern plot (STEPP) with a sliding window target size of 200 patients. An exploratory assessment of EGFR gene copy number gain was performed in tissue sections using fluorescence in situ hybridization (FISH) (J Clin Pathol; 2009;62(11):970-7). Efficacy outcomes were estimated using the Kaplan-Meier method and hazard ratios estimated using an un-stratified Cox model. .

      Results:
      A total of 982 patients (89.8% of the ITT) had evaluable IHC assay results. The large majority of these patients (95.2%) had tumor samples expressing EGFR protein; only 4.8% had tumors without detectable EGFR protein (H-score=0). The STEPP analyses showed no consistent trend or obvious cut-point for the relationship between either OS or PFS with EGFR protein across the range of IHC values when comparing treatment arms. Archived tumor tissue with evaluable results for exploratory EGFR FISH analysis was available for 51.0% of patients (557 of 1093 ITT patients). Of these patients, 208 patients (37.3%) had increased EGFR gene copy number (FISH positive). A trend for greater necitumumab benefit was observed in EGFR FISH positive patients. Treatment HR (95% CI) for FISH positive and negative patients were 0.70 (0.52, 0.96) and 1.02 (0.80, 1.29) for OS, and 0.71 (0.52, 0.97) and 1.04 (0.82, 1.33) for PFS. However, the interaction of EGFR gene copy number gain with treatment was not statistically significant for either OS or PFS (p=0.066 and 0.057, respectively).

      Conclusion:
      The analysis of EGFR protein expression did not identify consistent trends related to efficacy outcomes across the range of IHC values. EGFR gene copy number gain showed a trend for a more favorable HR, but did not appear to be strongly predictive. However, both markers showed some evidence of potential trends that will be investigated further in future trials.

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    ORAL 33 - ALK (ID 145)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 2
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      ORAL33.03 - Updated Efficacy/Safety Data From the Phase 2 NP28761 Study of Alectinib in ALK+ NSCLC (ID 1261)

      M.A. Socinski

      • Abstract
      • Presentation
      • Slides

      Background:
      ALK gene rearrangements occur in approximately 3–6% of patients with non-small-cell lung cancer (NSCLC). Crizotinib has demonstrated efficacy in ALK+ NSCLC, however many patients experience systemic and/or central nervous system (CNS) disease progression within one year of treatment. Alectinib, a CNS-penetrant and highly selective ALK inhibitor, has shown preclinical activity in the CNS (Ou, et al. JTO 2013) and clinical efficacy in crizotinib-naïve (Ohe, et al. ASCO 2015) and pre-treated (Ou, et al. ASCO 2015; Gandhi, et al. ASCO 2015) ALK+ NSCLC patients. We will present updated efficacy and safety outcomes from the phase II NP28761 study (NCT01871805).

      Methods:
      North American patients ≥18 years of age with ALK+ NSCLC (by FDA-approved FISH test), disease progression following first-line crizotinib, and ECOG PS ≤2 were enrolled. Patients received oral alectinib (600mg) twice daily until progression, death or withdrawal. The primary endpoint was overall response rate (ORR) by independent review committee (IRC) using RECIST v1.1. Secondary endpoints included investigator-assessed ORR; progression-free survival (PFS); quality of life (QoL); CNS response rate; disease control rate (DCR); and safety.

      Results:
      At data cut-off (24 October 2014), 87 patients were enrolled in the intent-to-treat population. Median age was 54 years; 74% had received prior chemotherapy; 60% of patients had baseline CNS metastases, of whom 65% (34/52) had prior brain radiation therapy. Median follow-up was 20.7 weeks. ORR by IRC was 48% (95% CI 36–60); median PFS was 6.3 months (Table 1). In patients with measurable CNS lesions at baseline (n=16), IRC CNS ORR was 69% (95% CI 41–89) and CNS DCR was 100% (complete response, 13%; partial response, 56%; stable disease, 31%). In patients with measurable or non-measurable CNS disease (n=52), IRC CNS ORR was 39% (95% CI 25–53) and 11 patients (21%) had complete CNS responses. The most common grade ≥3 AEs were elevated levels of blood creatine phosphokinase (8%), alanine aminotransferase (6%) and aspartate aminotransferase (5%); no GI toxicities leading to treatment withdrawal were reported. Clinically meaningful improvements were seen in EORTC QLQ-C30 items, including Global Health Status. Figure 1



      Conclusion:
      Alectinib (600mg twice daily) was well tolerated and demonstrated clinical efficacy in patients with ALK+ NSCLC disease who had progressed on prior crizotinib. A clinical benefit with alectinib was also observed in patients with CNS lesions at baseline. These data are preliminary; updated efficacy and safety data from a cut-off date of 27 April 2015 will be presented.

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      ORAL33.05 - Pooled Analysis of CNS Response to Alectinib in Two Studies of Pre-Treated ALK+ NSCLC (ID 1219)

      M.A. Socinski

      • Abstract
      • Presentation
      • Slides

      Background:
      The central nervous system (CNS) is a frequent site of progression in ALK+ NSCLC patients treated with crizotinib, thus good CNS efficacy is of crucial importance for new ALK inhibitors. Two recent phase II studies examined the efficacy and safety of alectinib in patients with ALK+ NSCLC who progressed after crizotinib; data from both studies were pooled to further examine the efficacy of alectinib in the CNS.

      Methods:
      Both phase II, single-arm, multicenter studies enrolled ALK+ NSCLC patients previously treated with crizotinib. One study was conducted in North America only (NP28761; NCT01871805), the other was global (NP28673; NCT01801111). All patients received 600mg oral alectinib twice daily. A primary endpoint of both studies was objective response rate (ORR) by independent review committee (IRC) and key secondary endpoints included CNS ORR by IRC and CNS duration of response (DOR). Response was determined according to RECIST v1.1. All patients underwent imaging at baseline to assess CNS metastases.

      Results:
      The pooled analysis population comprised 225 patients (n=87 from NP28761 and n=138 from NP28673); baseline characteristics were similar to each study population, with most patients being non-smokers, <65 years old with ECOG performance status 0/1. Median follow-up was 27.7 weeks. Fifty patients had measurable CNS disease at baseline (MD) while a further 85 had non-measurable disease (NMD) at baseline; both groups together (M+NMD) comprised 135 patients, 60% of the overall study population. In the MD group, 34 patients (68%) had received prior radiotherapy, but 24 of them had completed that radiotherapy >6 months prior to starting alectinib. For the M+NMD group, 94 patients (70%) had received prior radiotherapy, with 55 completing this >6 months prior to starting alectinib. In the MD group, 30/50 patients had a CNS response (60.0%; 95% CI 45.2–73.6%), with 7 complete responses (CR; 14.0%) and a CNS DCR of 90.0% (78.2–96.7%). In the M+NMD group, 22 additional patients had a CR (29/135; 21.5%), giving a CNS ORR of 38.5% (30.3–47.3%), with a CNS DCR of 85.2% (78.1–90.7%). Complete responses were seen in patients with and without prior radiotherapy. Median CNS DOR after only 17% of events in both groups was 7.6 months (5.8–7.6) in the MD group (n=30) and 7.6 months (5.8–10.3) in the M+NMD group (n=52), which is similar to the systemic DOR reported in both studies (Ou et al, ASCO 2015; Gandhi et al, ASCO 2015). Tolerability was also similar to the overall study population.

      Conclusion:
      Alectinib showed promising efficacy in the CNS in ALK+ NSCLC patients previously treated with crizotinib, achieving a complete response rate of 22% and a DCR of 85%, irrespective of prior radiotherapy. The CNS response was sustained for an equivalent duration to the systemic response, suggesting that alectinib could provide an effective treatment for patients with ALK+ NSCLC while actively targeting CNS metastases. The ongoing phase III clinical studies will assess the systemic and CNS efficacy of alectinib versus crizotinib as front-line therapy for ALK+ NSCLC patients.

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    P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 2
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      P1.01-062 - Rash as a Marker for the Efficacy of Necitumumab in the SQUIRE Study (ID 97)

      M.A. Socinski

      • Abstract
      • Slides

      Background:
      SQUIRE, a randomized, phase III study (n=1,093), demonstrated that the addition of the EGFR monoclonal antibody necitumumab (N) to gemcitabine-cisplatin (GC) improved overall survival in patients with stage IV squamous NSCLC. Rash is an established class side-effect associated with EGFR-targeting agents. Previous studies have suggested a positive association between rash and clinical outcomes with EGFR-targeted therapy.

      Methods:
      Pre-emptive treatment for rash was not allowed per protocol until completion of the first cycle of study therapy. For the purpose of this analysis, patients randomized to the N+GC arm were categorized and grouped according to whether or not they experienced rash during the first two cycles of study therapy. Patients who died or were lost to follow-up before completing two cycles of study therapy were not included in this analysis. Overall survival (OS) and progression-free survival (PFS) were measured from the date of randomization, with parameters estimated using the Kaplan-Meier method. Hazard ratios and 95% CIs between subgroups were estimated from stratified Cox proportional hazards models, with comparisons between arms using a stratified log-rank test.

      Results:
      505 patients were evaluable in the N+GC arm at the end of cycle 2 of which 69% experienced rash during cycle 1 and/or cycle 2. Patients experiencing rash in the N+GC arm had improved OS (HR=0.738, p=0.0001) and PFS (HR=0.808, p=0.0066) compared with patients in the GC arm. Patients experiencing rash in the N+GC arm had improved OS (HR=0.656, p=0.0001) compared with patients in the N+GC arm who did not experience rash. The difference in PFS between patients in the N+GC arm experiencing rash versus those not experiencing rash was not statistically significant. Median PFS and OS for patients experiencing rash in the N+GC arm was 6.2 mo and 13.6 mo respectively, as compared to 5.6 and 10.2 mo for patients in the N+GC arm without rash and 5.6 and 10.6 mo for patients in the GC arm.

      Patients alive and under follow-up after Cycle 2
      N+GC with rash N=350 N+GC no rash N=155 GC N=508
      Overall Survival, mo (CI) 13.6 mo (11.6, 15.2) 10.2 (8.7, 11.6) 10.6 (9.5, 11.9)
      HR* (95% CI) 0.656 (0.529, 0.813) 0.738 (0.631, 0.864)
      Stratified log-rank p value* 0.0001 0.0001
      PFS, mo (CI) 6.2 mo (5.7, 6.9) 5.6 (5.0, 5.7) 5.6 (5.3, 5.6)
      HR* (95% CI) 0.867 (0.693, 1.084) 0.808 (0.692, 0.942)
      Stratified log-rank p value* 0.2127 0.0066
      *In comparison to the N+GC group with rash

      Conclusion:
      Rash occurring during the first two cycles of treatment with necitumumab (N+GC) is associated with improved OS in patients with advanced squamous NSCLC.

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      P1.01-079 - Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone as First-Line Therapy for NSCLC (ID 2993)

      M.A. Socinski

      • Abstract
      • Slides

      Background:
      Platinum doublet chemotherapy with or without bevacizumab is the standard first-line therapy for patients with advanced NSCLC without EGFR sensitizing mutations or ALK rearrangement. Pembrolizumab (MK-3475), a humanized monoclonal antibody against PD-1 designed to block the interaction of PD-1 with its ligands PD-L1 and PD-L2, has shown efficacy and a manageable toxicity profile in patients with NSCLC treated at doses ranging from 2 mg/kg every 3 weeks to 10 mg/kg every 2 weeks. In 45 patients with treatment-naive advanced NSCLC treated in KEYNOTE-001, single-agent pembrolizumab has demonstrated a response rate of 26%.

      Methods:
      KEYNOTE-021 (ClinicalTrials.gov, NCT02039674) is an international, open-label, multi-arm, phase 1/2 trial of pembrolizumab for advanced NSCLC. After establishing the safety and tolerability of pembrolizumab plus carboplatin and pemetrexed in phase 1, a randomized phase 2 cohort comparing the efficacy of pembrolizumab plus carboplatin and pemetrexed with that of carboplatin and pemetrexed has been initiated. Key eligibility criteria for this cohort are previously untreated stage IIIB/IV nonsquamous NSCLC, no sensitizing EGFR mutation or ALK rearrangement, and ECOG PS 0-1. Patients will be randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg Q3W plus carboplatin and pemetrexed at standard doses or carboplatin and pemetrexed alone. Randomization will be stratified by PD-L1 expression determined by immunohistochemistry at a central laboratory (positive [membranous expression in ≥1% of tumor cells] vs negative). Pembrolizumab will be given for 24 months or until progression, intolerable toxicity, or investigator decision. Pembrolizumab may be continued beyond radiographic progression in eligible patients. Carboplatin and pemetrexed will be given for 4 cycles followed by maintenance pemetrexed, alone or with pembrolizumab. Patients allocated to the chemotherapy-alone arm who experience progression may cross over to the pembrolizumab arm of the study. AEs will be monitored throughout treatment and for 30 days thereafter. Response will be assessed every 6 weeks for the first 18 weeks, then every 9 weeks in year 1 and every 12 weeks in year 2. Survival follow-up will occur every 3 months after discontinuation of study treatment. Primary end point is progression-free survival (RECIST v1.1, central review); secondary end points include overall survival, objective response rate, and correlation of PD-L1 expression with antitumor activity. This cohort is currently enrolling patients.

      Results:
      Not applicable.

      Conclusion:
      Not applicable.

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    P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 3
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      P2.01-065 - <em>nab</em>-Paclitaxel + Carboplatin in Advanced NSCLC: Analysis of Age and Renal Function (ID 1559)

      M.A. Socinski

      • Abstract
      • Slides

      Background:
      Renal impairment increases with age and can impact treatment decisions. In a phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) significantly improved the overall response rate (ORR; primary endpoint) compared with solvent-based paclitaxel plus C (sb-P/C) in patients with advanced NSCLC (Socinski et al. J Clin Oncol. 2012;30:2055-2062). In a subgroup analysis of this phase III trial, nab-P/C demonstrated promising efficacy and was well tolerated in patients with or without renal impairment (Langer et al. Clin Lung Cancer. 2015;16:112-120). This analysis examined outcomes of patients in the phase III trial stratified by age and renal function.

      Methods:
      Patients with histologically or cytologically confirmed stage IIIB/IV NSCLC and no prior chemotherapy for metastatic disease received either nab-P 100 mg/m[2] on days 1, 8, and 15 or sb-P 200 mg/m[2] on day 1 in combination with C AUC 6 on day 1 every 21 days (randomized 1:1). Treatment continued until disease progression. Baseline renal function (creatinine clearance [CrCl]) was assessed in a central lab. ORR and progression-free survival (PFS) were assessed by blinded, centralized review. P values for ORR were based on the chi-square test, and those for overall survival (OS) and PFS were based on the log-rank test.

      Results:
      Treatment with nab-P/C resulted in improved outcomes compared with sb-P/C in patients with mild renal impairment, regardless of age (Table). nab-P/C also consistently demonstrated greater treatment effect compared with sb-P/C for ORR and similar or better PFS and OS in patients ≥ 60 years, regardless of renal function. In patients with either mild renal impairment or normal renal function, the toxicity profiles in each treatment arm were similar to those of the intent-to-treat population.

      Conclusion:
      These results suggest that, in general, clinical outcomes in patients with advanced NSCLC and mild renal impairment are better with nab-P/C vs sb-P/C, regardless of age. It should be noted that these were small subset analyses and results should be interpreted with caution. Figure 1



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      P2.01-090 - A Phase 2, Single Arm Study of Lucitanib in Patients with Advanced/Metastatic Lung Cancer and FGF, VEGF, or PDGF-Related Genetic Changes (ID 2878)

      M.A. Socinski

      • Abstract
      • Slides

      Background:
      Lucitanib is a potent, oral inhibitor of the tyrosine kinase activity of Fibroblast Growth Factor Receptors 1-3 (FGFR1-3), Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR1-3) and Platelet-Derived Growth Factor Receptors A/B (PDGFRA/B). Clinical activity was observed in a phase 1/2 study of lucitanib monotherapy in cancer patients with tumor amplification of FGF-related genes or in tumors with predicted sensitivity to VEGF inhibitors. Genomic evidence of FGF, VEGF or PDGF axis aberrancy is seen in up to 15% of patients with lung cancer, which provides a strong rationale to assess lucitanib in this setting.

      Methods:
      The current study evaluates daily oral lucitanib monotherapy in 40 patients with amplification or activating mutations in FGF, VEGF or PDGF-related genes. This is an international, multicenter, open-label, single-arm study. The primary endpoint is objective response rate (ORR; RECIST 1.1) with secondary endpoints of response duration, clinical benefit rate, progression-free survival, and safety. Exploratory objectives include volumetric assessment of tumor growth kinetics, serial circulating tumor DNA measurement, and identification of additional biomarkers of lucitanib activity. Key inclusion criteria include: patients with advanced/metastatic non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) or large cell lung cancer and tumor tissue evidence of relevant genomic aberrancies. Patients must have measurable disease and at least one previous treatment for advanced disease. Key exclusion criteria include: carcinoid histology, symptomatic CNS metastases, anti-cancer treatment for lung cancer within 28 days or 5 half-lives before first dose of lucitanib. This study is enrolling patients in the United States and Europe at centers skilled in the identification of patients with relatively uncommon genetic tumor alterations.

      Results:
      not applicable

      Conclusion:
      not applicable

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      P2.01-095 - <em>nab</em>-Paclitaxel/Carboplatin Followed By <em>nab</em>-Paclitaxel for NSCLC PS 2 (ABOUND.PS2) (ID 955)

      M.A. Socinski

      • Abstract
      • Slides

      Background:
      Many patients with advanced non-small cell lung cancer (NSCLC) often present with poor performance status (PS), and there is no clear consensus on how best to treat these patients. Despite an increased risk of toxicity resulting from standard chemotherapy, patients with NSCLC and a poor PS can clinically benefit from platinum-doublet therapy. In a multicenter phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) in patients with NSCLC and an ECOG PS 0-1 significantly improved the overall response rate (ORR) compared with solvent-based paclitaxel plus C (33% vs 25%; P = 0.005; Socinski et al. J Clin Oncol. 2012;30:2055-2062). In the single-arm, open-label, multicenter phase II ABOUND.PS2 study, the safety and efficacy of first-line nab-P/C followed by nab-P monotherapy will be evaluated in patients with locally advanced/metastatic NSCLC and an ECOG PS of 2.

      Methods:
      During the induction part of the study, approximately 50 patients will be treated with 4 cycles of nab-P 100 mg/m[2] intravenously (IV; 30-minute infusion) on days 1 and 8 plus C AUC 5 IV on day 1 every 21 days. Patients without disease progression may proceed to the monotherapy part of the study in which they will continue to receive nab-P 100 mg/m[2] IV (30-minute infusion) on days 1 and 8 every 21 days until progression or unacceptable toxicity. Key eligibility criteria include histologically/cytologically confirmed stage IIIB/IV NSCLC, no prior chemotherapy for metastatic disease, ECOG PS of 2, adequate organ function, no active brain metastases, and preexisting peripheral neuropathy grade < 2. ClinicalTrials.gov number NCT02289456.

      Key Endpoints
      Primary The percentage of patients who discontinue treatment during the induction part due to treatment-emergent adverse events
      Secondary Safety Progression-free survival Disease control rate Overall survival ORR
      Exploratory Healthcare resource utilization throughout the study Changes in physician-reported ECOG PS and patient-reported quality of life Summary of Charlson Co-Morbidity Index at baseline Correlation between patient- and physician-reported ECOG PS during treatment Correlation between patient- and physician-reported Karnofsky PS at baseline


      Results:
      This is a TPS abstract Results = NA

      Conclusion:
      This is a TPS abstract Results = NA

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    P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 2
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      P3.01-058 - <em>nab</em>-Paclitaxel + Carboplatin in Advanced Non-Small Cell Lung Cancer NSCLC: Dose Modification Analysis (ID 1570)

      M.A. Socinski

      • Abstract
      • Slides

      Background:
      Chemotherapy dose modifications may impact clinical outcomes in patients with cancer. In a phase III trial, first-line treatment of patients with advanced NSCLC with nab-paclitaxel plus carboplatin (nab-P/C) significantly improved the overall response rate (ORR; primary endpoint) compared with solvent-based paclitaxel plus C (sb-P/C; 33% vs 25%; P = 0.005; Socinski et al. J Clin Oncol. 2012;30:2055-2062). This exploratory analysis examined the correlation between patients receiving protocol-specified dose modifications and clinical outcomes in the phase III trial.

      Methods:
      Patients with histologically or cytologically confirmed stage IIIB/IV NSCLC and no prior chemotherapy for metastatic disease received either nab-P 100 mg/m[2] on days 1, 8, and 15 or sb-P 200 mg/m[2] on day 1, both in combination with C AUC 6 on day 1, every 21 days (randomized 1:1). ORR and progression-free survival (PFS) were assessed by blinded, centralized review. P values for ORR were based on the chi-square test, and those for overall survival (OS) and PFS were based on the log-rank test. Patients who discontinued treatment before cycle 3 or remained on treatment after 6 months were excluded from this analysis unless otherwise specified.

      Results:
      Dose modification and clinical outcomes for patients treated for ≥ 3 cycles but ≤ 6 months are shown in the Table. In the nab-P/C arm, 268 of 310 patients (86%) who were treated for ≥ 3 cycles and ≤ 6 months had a dose modification compared with 200 of 319 (63%) in the sb-P/C arm. In the nab-P/C cohort, ORR and PFS were significantly higher in patients who received a dose modification vs those who did not (Table), possibly due to better tolerability and longer treatment duration. In the sb-P/C arm, there were no differences in efficacy outcomes between either group. As predicted, patients with a lower numerical incidence of toxicity were those that did not require dose modifications.

      Conclusion:
      This exploratory analysis suggested that, in this patient subset, protocol-specified dose modifications did not negatively impact the primary endpoint of ORR and in fact resulted in a greater ORR for those receiving nab-P/C. Figure 1



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      P3.01-072 - Final Efficacy and Safety Results of ECOG Performance Status (PS) Subgroup Analyses From the SQUIRE Phase III Study (ID 1660)

      M.A. Socinski

      • Abstract
      • Slides

      Background:
      As previously reported, the SQUIRE study demonstrated that the addition of necitumumab (N) to gemcitabine-cisplatin (GC) chemotherapy significantly improved survival in patients with stage IV squamous NSCLC. Overall survival (OS), progression-free survival (PFS), and safety results are presented for Eastern Cooperative Oncology Group (ECOG) PS 0–1/2 subgroups.

      Methods:
      Patients with stage IV squamous NSCLC were randomized 1:1 to N (800 mg iv, days 1 and 8) plus GC (G=1250 mg/m² iv, days 1 and 8; C=75 mg/m² iv, day 1) or GC alone every 21 days for up to six cycles in this multicenter, open-label study. N+GC patients without progression continued on N alone until progressive disease or intolerable toxicity. The study was powered for OS and PFS (previously reported). Preplanned subgroup analyses were performed for ECOG PS 0–1 and 2.

      Results:
      Subgroups PS 0–1/2 (n=996 [91%]/n=96 [9%]) were well balanced regarding baseline characteristics (males, 83% vs 86%; median age, 62 vs 65 yrs; smoking/ex-light smoker/nonsmoker, 91/4/5% vs 89/6/5%). GC median relative dose intensity was similar between PS 0–1/2 subgroups; N (overall) was higher for the PS 0–1 than for PS 2 subgroup (94.8% and 90.0%). Post-study therapy use was generally higher in the PS 0–1 than in the PS 2 subgroup, but was balanced between both arms. The OS hazard ratio (HR) for N+GC vs. GC was 0.85 (95% CI: 0.74, 0.98; p=0.026) for PS 0–1 and 0.78 (95% CI: 0.51, 1.21; p=0.275) for PS 2. The PFS HR (N+GC vs. GC) was 0.86 (95% CI: 0.75, 0.99; p=0.035) for PS 0–1 and 0.79 (95% CI: 0.50, 1.24; p=0.292) for PS 2. Select Grade ≥3 treatment-emergent adverse events (TEAEs) are shown in the table. The percentage of patients with adverse events leading to discontinuation of any study drug was lower in the PS 0–1 subgroup (N+GC=30%; GC=23%) than the PS 2 subgroup (N+GC=42%; GC=41%). The percentage of patients hospitalized was higher in the PS 0–1 subgroup (N+GC=43%; GC=34%) than the PS2 subgroup (N+GC=25%; GC=30%). Table. Select TEAEs

      Grade ≥3 Event* PS 0-1 N+GC (%) N=490 PS 0-1 GC (%) N=495 PS 2 N+GC (%) N=48 PS 2 GC (%) N=46
      Neutropenia 25.5 28.1 12.5 21.7
      Febrile neutropenia 0.6 1.4 2.1 0
      Anemia 11.2 10.3 4.2 17.4
      Thrombocytopenia 10.4 10.5 8.3 13.0
      Fatigue 7.1 7.1 8.3 6.5
      Hypomagnesemia 9.8 1.0 4.2 2.2
      Rash 7.8 0.4 0 0
      Arterial thromboembolic events 3.7 1.8 6.3 4.3
      Venous thromboembolic events 5.5 2.6 0 2.2
      [*][Adverse events of possible relevance to treatment, according to either composite categories or preferred terms (febrile neutropenia only)]

      Conclusion:
      OS and PFS treatment results for N+GC were consistent and considered favorable across subgroups including ECOG PS 2 patients. Administration of N+GC was well tolerated in PS 2 patients, with no evidence of an increased safety risk in this subgroup.

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