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O. Gautschi

Moderator of

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    SC04 - EGFR Tyrosine Kinase Inhibitors: A Model for Successful Drug Development (ID 328)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 4
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      SC04.01 - First- and Second Generation EGFR Tyrosine Kinase Inhibitors (ID 6613)

      11:00 - 12:30  |  Author(s): J.C. Yang

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      SC04.02 - Management of Resistance to EGFR Tyrosine Kinase Inhibitors (ID 6614)

      11:00 - 12:30  |  Author(s): T. Mitsudomi

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Discovery of activating mutations of the EGFR gene in adenocarcinoma of the lung in 2004 opened the door to a new era for personalized therapy in thoracic oncology. Lung cancers with EGFR mutation are highly sensitive to EGFR-tyrosine kinase inhibitors (TKI) such as gefitinib, erlotinib, or afatinib, resulting in significantly prolonged progression free survival compared with those treated with platinum doublet chemotherapy. However, acquired resistance inevitably develops usually after a median of 10~12 months. The mechanisms for this resistance have been extensively studied and can be classified into 1) target gene alteration, 2) activation of bypass / accessory pathway, and 3) histologic transformation (Fig.).Figure 1 The most common (50~60%) mechanism for acquired resistance to the EGFR-TKI is a missense mutation at codon 790 of the EGFR gene resulting in substitution of threonine to methionine (T790M). This amino acid change reduces affinity between EGFR kinase and EGFR-TKI compared with that between EGFR-kinase and ATP, leading to reactivation of down-stream pathways. L747S, D761Y, and T854A are also known as secondary mutations that cause acquired resistance, but they are very rare. In these cases, cancer cells are still addicted to or dependent on EGFR pathway. Amplification of the MET gene which codes for a receptor of hepatocyte growth factor (HGF) was the first that was identified as a bypass track resistance mechanism against EGFR-TKI. Following this report, aberrant activation of other receptor tyrosine kinases such as HER2, HER3, AXL, IGF1R, have been reported. It is also shown that some ligands for the receptor tyrosine kinases such as HGF, FGF or IGF cause acquired resistance to EGFR-TKIs. Similarly, alteration of downstream molecule cause resistance. These molecules include BRAF, PTEN, JAK2, CRKL, DAPK, NF-kB, or PUMA. The third mechanism of acquired resistance is histologic transformation that includes small cell lung cancer transformation and epithelial-mesenchymal transition EMT). Exact mechanisms of these histologic changes are not fully understood. However, AXL, Notch-1, TGFb pathway activation as well as down regulation of MED12 ((Mediator Complex Subunit 12) have been proposed as mechanisms of EMT. Then, How are we able to cope with these resistance? For T790M gatekeeper mutations, the third generation EGFR inhibitors that selectively inhibit EGFR-T790M while sparing the wild-type EGFR are active. One of these drugs, osimertinib is already approved and gives a response rate of ~60% and progression free survival of ~11 months. Therefore, identification of T790M at the time of disease progression by rebiopsy is important. We have recently found that three other secondary EGFR mutations implicated in acquired resistance are also sensitive to osimertinib. Tumor resistance caused by activation of accessory pathways can be theoretically coped with by combination of the inhibitor of EGFR and involved molecules. However, because of rarity of each mechanism, there is no clear evidence whether these combination therapies will actually improve patient outcome In other cases, cytotoxic chemotherapy is still an important strategy. According to the IMPRESS study, median progression free survival for patients without T790M who received cisplatin plus pemetrexed was 5.4 months. Eeven with these strategies, cancer cells are smart enough to escape from the therapy using other mechanisms. Heterogeneities in terms of resistant mechanisms within a single patient become evident when specific therapeutic pressure persists. Therefore, we also need to have armamentarium that utilizes other mechanisms to cure lung cancer. Recent advances of immunotherapy targeting immune checkpoints appear attractive in this respect. These mechanism-driven therapeutic approaches will convert this fatal disease into a more chronic disorder, and eventually into a curable disease with the least patient burden.



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      SC04.03 - Sequencing of EGFR Tyrosine Kinase Inhibitors (ID 6615)

      11:00 - 12:30  |  Author(s): K. Park

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Figure 1. Sequence of EGFR TKIsFigure 1 Sequencing of EGFR Tyrosine Kinase Inhibitors Keunchil Park, MD, PhD Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Treatment of EGFR-mutant(EGFRm) lung cancer with specific EGFR TKIs, such as gefitinib, erlotinib or afatinib, has opened the door to the precision medicine in the management of advanced non-small cell lung cancer with remarkable tumour shrinkage and improvement in progression-free survival (PFS) and quality of life compared to standard chemotherapy. Despite such a remarkable initial clinical response with EGFR TKIs in patients with EGFR+ NSCLC, however, the disease eventually comes back with the emergence of acquired resistance and median PFS is ~ 1 year. The most common mechanism of resistance is acquisition of the T790M gatekeeper mutation and the 3rd-generation EGFR TKIs irreversibly inhibit mutant EGFR, esp. T790M, with sparing wild-type(WT) EGFR. There are several EGFR mutant specific inhibitors(EMSIs) under development including AZD9291, CO-1686, BI1482694 /HM61713, ASP8273, etc. All these 3rd-generation EGFR TKIs have shown a promising early clinical efficacy in T790M(+) EGFRm NSCLC patients with ORR of ca. 60% and PFS of 9.6 – 10.3 months and appear to be well tolerated. Based upon these encouraging early results many confirmatory phase 3 trials(e.g., NCT02151981, NCT02322281) comparing to the standard chemotherapy in the 2nd-line setting are underway. It is very tempting that one might like to move the 3rd-generation EGFR TKI to 1st-line setting. The development of the 3rd-generation agents as the first-line therapy for patients with EGFRm disease has already started. Recently AZD9291 demonstrated an encouraging clinical activity and a manageable tolerability profile in 1st-line: confirmed objective response rate of 77% (95% CI 64, 87) and mPFS of 19.3 months (investigator-assessed). Currently it is being compared with the 1st/2nd-generation EGFR TKI in the 1st-line setting. The Phase III FLAURA study (NCT02296125), comparing AZD9291 80 mg once daily versus current standard of care EGFR-TKIs for treatment-naïve patients, is enrolling. Though the preliminary result in the 1L setting is quite provocative, extreme caution needs to be exerted since the currently available data are not mature enough to determine which agent is the best in its class and only from a small subset of patients. Though it is hoped that the T790M-mediated resistance can be delayed or prevented by using the EMSIs in the TKI-naïve setting, it is also possible that other less well known escape mechanisms might emerge. Given that EMSI works well after failing 1st/2nd-generation EGFR TKI I believe it seems to be a more reasonable approach to investigate if EMSI in the TKI-naïve setting is more effective than 1st/2nd-generation EGFR TKI followed by EMSI when failing 1st/2nd-generation EGFR TKI with acquired resistance. One of the biggest questions to emerge in the era of next-generation inhibitors that have activity against the basic driver oncogene is whether it makes sense to use this approach before the development of acquired resistance to prevent it from occurring in the first place. Can its use in the 1st-line(TKI-naïve) setting prevent the development of acquired resistance and lead to a longterm control of the disease? Considering the well-known genomic heterogeneity with its possible association with resistance to EGFR TKIs we need better understanding of the biology and resistance mechanisms to this class of new generation EGFR TKIs in order to develop better strategies for subsequent therapies to overcome the resistance including how to best sequence the available EGFR TKIs in the clinic as well as combination therapies. It is fair to say that during the past few years we’ve clearly made another progress in the management of NSCLC patients with EGFRm, including those who failed previous EGFR TKIs. However, the currently available data are not mature enough to determine which agent is the best in its class, with the notable differences primarily related to toxicity and we’re not there yet and still lots of unanswered questions remain and further researches are warranted. References 1. DR Camidge, et al. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol 2014;11: 473–481 2. SS Ramalingam, et al. The Next Generation of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Lung Cancer. Cancer 2015;121:E1-E6 3. GR Oxnard et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M. Nature Med 2015;21:560-564 4. LV Sequist et al. Heterogeneity Underlies the Emergence of EGFR T790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor . Cancer Discov 2015;5(7): 713–22 5. CM Lovly et al. Shades of T790M: Intratumor Heterogeneity in EGFR -Mutant Lung Cancer. Cancer Discov 2015;5(7): 694–6. 6. S Ramalingam, et al. ELCC 2016; Abstract LBA1_PR



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      SC04.04 - Liquid Biopsies for Dynamic Monitoring of EGFR Mutations in Lung Cancer (ID 6616)

      11:00 - 12:30  |  Author(s): M. Schuler

      • Abstract
      • Slides

      Abstract:
      Somatic mutations clustering in exons 18 to 21 of the EGFR gene characterize distinct lung cancer biologies. Patients with metastatic EGFR-mutated lung cancer are exquisitely sensitive to targeted agents inhibiting the EGFR tyrosine kinase, which have demonstrated superior progress-free survival and, in some instances, overall survival when compared to platinum-based chemotherapy in first-line treatment. Several studies have shown that EGFR mutations can be detected by highly sensitive assay technology in free DNA circulating in the blood from patients with EGFR-mutated lung cancers 1,2,3. Circulating EGFR-mutated DNA may drop below the level of detection in patients responding to EGFR-TKI, and persistence or reoccurrence of circulating EGFR-mutated DNA may associate with primary and acquired resistance 1,3. In addition, clonal evolution of EGFR-mutated lung cancers under EGFR-TKI therapy can be mirrored by the detection of gatekeeper mutations, such as EGFR T790M or the EGFR C797S, in circulating DNA 4,5. Hence, mutation analysis in circulating free DNA has been suggested as a clinically more feasible and less invasive method for detection of predictive genomic biomarkers and treatment monitoring in advanced lung cancer. The development of more sensitive technologies and bioinformatic algorithms enables the study of comprehensive genomic biomarker panels in blood-derived DNA, which cover a broader spectrum of actionable mutations in treatment-naïve patients and those with acquired TKI resistance. Currently, there are still several limitations to overcome. First, the predictive value of a mutation detected in blood-derived DNA cannot be simply extrapolated from validation studies conducted with tumor-derived DNA. In consequence, prospective clinical validation of blood-based biomarkers is mandatory. Secondly, most studies comparing EGFR mutation detection in tumor and “liquid” biopsies side-by-side reveal inferior sensitivity of blood-based assays. Also, there is a considerable degree of discordance between such assays 4,6,7. Thus, “negative” findings in circulating tumor DNA have to be confirmed by a second assay in tumor-derived DNA. Apart from inflating spending on molecular diagnostics, this may result in further treatment delays, which is hard to bear for patients in particular in the first-line setting. While these obstacles may be soon overcome by technological advances and evolving data from validation studies, “liquid biopsies” focusing on DNA and/or RNA will always miss out on the histopathological information that can be derived from a biopsy of a tumor or metastasis. In the era of immunomodulatory antibody therapy information of tumor-infiltrating immune and stromal cells as well as expression of biomarkers by specific cell populations or with spatial variation become increasingly important. Until this information cannot be reproducibly derived by novel assay technologies the detection of genomic biomarkers in blood-derived DNA will become a highly valuable, additive modality for specific scenarios of primary diagnosis and treatment monitoring. References: 1 N Engl J Med. 2008 Jul 24;359(4):366-77. 2 Clin Cancer Res. 2009 Apr 15;15(8):2630-6. 3 PLoS One. 2014 Jan 21;9(1):e85350. 4 Lung Cancer. 2015 Dec;90(3):509-15. 5 Nat Med. 2015 Jun;21(6):560-2. 6 Clin Cancer Res. 2016 Mar 1;22(5):1103-10. 7 J Clin Oncol. 2016 Jun 27. pii: JCO667162.

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    MA16 - Novel Strategies in Targeted Therapy (ID 407)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      MA16.03 - Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers (ID 4325)

      14:20 - 15:50  |  Author(s): O. Gautschi

      • Abstract
      • Presentation
      • Slides

      Background:
      GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.

      Methods:
      A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).

      Results:
      165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.

      Conclusion:
      RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.

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    P3.02c - Poster Session with Presenters Present (ID 472)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02c-032 - Interstitial Pneumonitis Associated with Immune Checkpoint Inhibitors Treatment in Cancer Patients (ID 5670)

      14:30 - 15:45  |  Author(s): O. Gautschi

      • Abstract
      • Slides

      Background:
      Immunotherapy is now a standard of care in melanoma, lung cancer and is spreading across other tumours. Immune checkpoint inhibitors (ICI) are generally well tolerated but can also generate immune-related adverse effects. Since the first trials, pneumonitis has been identified as a rare but potentially life-threatening event.

      Methods:
      We conducted a retrospective study over a period of 5 months in centers experienced in ICI use in clinical trials, access programs or following national approval. We report the main features of possibly related pneumonitis occurring in patients treated with ICI with a particular focus on clinical presentation, radiologic patterns (with a double reviewing by radiologists and pulmonologists), pathology and therapeutic strategies.

      Results:
      We identified 71 patients with possibly related pneumonitis including 54 NSCLC and 13 melanoma. They mainly received PD1 inhibitors. Pneumonitis usually occurred in male, former or current smokers with a median age of 59 years. We observed grade 2/3 (n= 45, 65.2%) and grade 5 (n= 6, 8.7%) pneumonitis. The median duration time between the introduction of immunotherapy and the pneumonitis was 2.2 months [0.1-27.4]. Ground glass opacitiy on lung CT-scan were the most predominant lesion 80.9% (n=55), followed by consolidations 44.1% (n=30), reticulations 36.7% (n=25) and bronchiectasis in 20.6% (n=14). When performed, bronchoalveolar lavage (BAL) showed a T-lymphocytic alveolitis and transbronchial biopsy an inflammatory and lymphocytic infiltration. Pneumonitis treatment was steroids (86.6%) and/or antibiotics (67.6%). Immunotherapy was stopped after the pneumonitis for 65 cases (92.9%) and reintroduced for 12 (9.4%) cases. Twenty-four patients (34.3%) were dead at the last follow-up and 46 patients (65.7%) were still alive. Among the living patients, the pneumonitis outcome was a total recovery in 12 patients, improvement in 22 patients, stability in 10 patients, worsening evolution in 1 patient (1 unknown). Causality of immunotherapy was evaluated by investigators as “possible” for 34 patients (49.3%), “probable” for 17 (24.6%), “certain” for 15 (21.7%) other causes for 3 (4.3%) and 2 unknowns. Median overall survival from the onset of pneumonitis was 6 months.

      Conclusion:
      This serie, the largest to date, of immune-related pneumonitis demonstrates that it occurs usually during the first months and displays specific radiologic features. As there is no clearly identified risk factor, oncologists should be able to detect, diagnose (with CT-scan and bronchoscopy) and treat this adverse event. An early management is usually associated with a favourable outcome and requires a close collaboration between pulmonologists, radiologists and oncologists.

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    P3.06 - Poster Session with Presenters Present (ID 492)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Trial Design/Statistics
    • Presentations: 1
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      P3.06-010 - Clinical Outcomes of Non-Small Cell Lung Cancer (NSCLC) Patients with ALK Co-Mutations (EGFR or KRAS) Receiving Tyrosine Kinase Inhibitors (TKI) (ID 4729)

      14:30 - 15:45  |  Author(s): O. Gautschi

      • Abstract

      Background:
      Anaplastic lymphoma kinase (ALK) rearrangements with concurrent epidermal growth factor (EGFR) or Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations occur very rarely. Outcomes with TKI in these patients (pts) are poorly understood.

      Methods:
      Outcomes of pts with metastatic NSCLC and double mutations of ALK/EGFR or ALK/KRAS detected by FISH (ALK) and PCR or NGS (EGFR/KRAS) from six oncology centres in Switzerland were retrospectively analysed.

      Results:
      A total of 15 pts with adenocarcinoma were identified, 53% were females and tumor stages were IIIB (6%), IVA (27%) and IVB (67%). Six pts had a co-mutation of ALK/EGFR and nine ALK/KRAS. ALK/EGFR pts were younger (54 vs. 64 years) and less likely to be (ex-) smokers (34% vs. 77%). In total, 12 pts received an ALK-TKI (11x crizotinib, 1x alectinib, 2x ceritinib, 1x lorlatinib). EGFR-TKIs were given to five EGFR/ALK pts (4x afatinib, 2x osimertinib, 3x erlotinib). 33% received > 1 ALK-or EGFR-TKI. TKI were given as first-line (1L) in 40% (4x ALK/KRAS, 2x ALK/EGFR). Pts with ALK/KRAS co-mutation: Seven of eight pts (88%) were primary refractory to ALK-TKI treatment (all crizotinib). One patient has ongoing disease stabilization since 26 months. Three of six pts responded to 1L platinum-based chemotherapy with a median progression free survival (PFS) of 4.25 months (range: 1 month - NR). Pts with ALK/EGFR co-mutation: Two of four pts responded to ALK-TKI: one PR to crizotinib+erlotinib combination, one PR to alectinib and lorlatinib. Median PFS on first ALK-TKI was 3.75 months (range: 1-7months). Three of five pts (60%) achieved one or more responses to EGFR-TKI in different lines of therapy (4x PR: 3x afatinib, 1x osimertinib, CR: 1x osimertinib). Median PFS on first EGFR-TKI was 4.5 months (range: 3-7 months). Two of five pts responded to platinum-based chemotherapy (median PFS: 5.5 months (range: 0.25-10 months)).

      Conclusion:
      De novo concurrent ALK/KRAS alterations are associated with resistance to ALK-TKI treatment in seven out of eight pts, although one patient achieved ongoing disease stabilization for 26 months. Thus, platinum-based chemotherapy should be 1L treatment for these patients. In ALK/EGFR pts outcomes with ALK and EGFR-TKI seem inferior to what would be expected in pts with either alteration. EGFR-TKIs may potentially be more active compared to ALK-TKIs in ALK/EGFR pts. Worse outcomes to ALK-TKI may partly be related to false-positive ALK test results. Further studies are needed to clarify which patients may still benefit from the respective TKI.

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    P3.07 - Poster Session with Presenters Present (ID 493)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Regional Aspects/Health Policy/Public Health
    • Presentations: 1
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      P3.07-001 - Nivolumab for Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer: A Cost-Effectiveness Analysis including PD-L1 Testing (ID 3741)

      14:30 - 15:45  |  Author(s): O. Gautschi

      • Abstract
      • Slides

      Background:
      Nivolumab (NIV) is approved in several countries for pre-treated patients with advanced non-small cell lung cancer (NSCLC). UK NICE previously reported that NIV is not cost-effective compared with DOC for the treatment of squamous NSCLC. Here, we report cost-effectiveness for nonsquamous NSCLC, and consequences of patient selection by PD-L1 testing.

      Methods:
      Based on the published results of the CheckMate-057 trial (Borghaei et al, NEJM 2015), we performed a literature-based health economic modelling study to estimate the incremental cost-effectiveness ratio (ICER) of NIV versus DOC for the Swiss health care setting. We estimated the probability of reaching cost-effectiveness based on a willingness to pay (WTP) threshold of CHF100’000 per QALY gained. Moreover, we implemented patient selection for NIV treatment using PD-L1 staining, and modelled the effect of reducing the NIV price, dose, and treatment duration, on the ICER.

      Results:
      In the base case model, NIV (mean costs CHF 66’208; mean effect 0.69 QALYs) compared to DOC (mean costs CHF 37'618; mean effect 0.53 QALYs) resulted in an ICER of CHF 177’478 per QALY gained. Selecting patients for NIV by PD-L1 testing (threshold ≥10%), resulted in a base case ICER of CHF124’891 per QALY gained, compared to treating all patients with DOC. Reduction of NIV price, dose, or treatment duration, all reduced the ICER partially below an assumed WTP of CHF100’000 per QALY (see Table 1). Cost-effectiveness was strongly influenced by health state utilities. Table 1 Results of the base case and scenario analyses

      Scenario Treatment arm Cost (mean) Effect Month (mean) Effect QALY (mean) Compared to Incremental costs Incremental effect ICER CHF probability cost- effective
      Base case DOC 37'618 10.99 0.53
      NIV 66’208 15.42 0.69 DOC 28’589 0.16 177’478 14.1%
      PD-L1 ≥1% 74'968 17.26 0.79 DOC 35’530 0.27 133’267 19.7%
      NIV 6'941 0.11 65’774 85.2%
      PD-L1 ≥10% 69’893 16.83 0.78 DOC 32’274 0.26 124’891 22.1%
      NIV 3’685 0.10 37’860 86.7%
      DOC= docetaxel, NIV=Nivolumab, QALY= quality adjusted life years, ICER= incremental cost effectiveness ratio, CHF=Swiss Francs

      Conclusion:
      At its current price, NIV is not cost-effective compared with DOC for the treatment of patients with nonsquamous NSCLC. Price reduction and/or patient selection by PD-L1 testing would be highly recommendable from a socio-economic viewpoint.

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    SC11 - ALK, ROS1 and Rare Mutations in NSCLC (ID 335)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      SC11.04 - Rare Mutations in Lung Cancer (ID 6644)

      16:00 - 17:30  |  Author(s): O. Gautschi

      • Abstract
      • Presentation
      • Slides

      Abstract:
      "Lung adenocarcinoma" is a genetically heterogenous disease entity, characterized by a wide spectrum of different mutations. Some of these mutations lead to constitutive activation of receptor tyrosine kinases, which can be inhibited by small molecules (tyrosine kinase inhibitors, TKIs). EGFR mutations (2004) and ALK rearrangement (2007) were among the first actionable driver mutations identified in lung adenocarcinomas. Today, several drugs are approved for the treatment of advanced lung adenocarcinomas with EGFR mutations or ALK/ROS1 rearrangement. Combined, these molecular subgroups make up at least 20% of all lung adenocarcinomas or more, depending on the poplulation. Further actionable driver mutations include the genes BRAF, HER2, MET, and RET. These genes are less frequently mutated than EGFR/ALK, nevertheless, rare drivers are clinically relevant because of the availability of targeted therapies approved for other indications in oncology (ALK-lung, HER2-breast, RET-thyroid, and BRAF-melanoma). The discussant will summarize current knowledge about rare driver mutations, with a strong clinical focus. HER2 insertion 20, present in about 1% of lung adenocarcinomas, was initially proposed by Cappuzzo et al as a potential indication for trastuzumab-based therapy [1]. Prospective trials with HER2 targeting drugs are currently ongoing. BRAF V600E, present in about 3% of lung adenocarcinomas, was associated with high activity of combined therapy with dabrafenib and trametinib in a prospective phase II trial by Planchard et al [2]. Crizotinib, recently approved by the FDA for the treatment of ROS1-NSCLC, is also active in tumors harboring MET exon 14 mutations as demonstrated by Drilon et al [3]. Cabozantinib and vandetanib are active in tumors with RET rearrangement as shown by three recent phase II trials [4-6]. Entrectinib showed preliminary activity in tumors harboring TRK rearrangement in an early basket Trial [7]. These results will be discussed in detail, together with the results of international registries (EUHER2, EURAF, EUROS1 and GLORY [8]). Moreover, current treatment recommendations for patients with advanced lung adenocarcinomas and rare driver mutations will be summarized. References 1. Cappuzzo et al. N Engl J Med. 2006;354(24):2619-21. 2. Planchard et al. Lancet Oncol. 2016;17(7):984-93. 3. Drilon et al. J Clin Oncol 34, 2016 (suppl; abstr 108) 4. Drilon et al. Cancer Discov. 2013;3(6):630-5. 5. Seto et al. J Clin Oncol 2016;34(suppl; abstr 9012) 6. Lee et al. J Clin Oncol 2016;34(suppl; abstr 9013) 7. Drilon et al. AACR 2016 (abstract CT007) 8. Gautschi et al. WCLC 2016 (abstract 4325)

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