Virtual Library

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    ISS03 - Symposium Supported by Springer Healthcare IME: Steering Improved Outcomes in Non-driver Mutation Lung Cancer: Progress and Challenges (Not IASLC CME Accredited) (ID 856)

    • Event: WCLC 2018
    • Type: Industry Supported Symposia
    • Track:
    • Presentations: 6
    • Moderators:
    • Coordinates: 9/23/2018, 13:00 - 14:30, Room 106
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      Welcome and Introduction (ID 12158)

      13:00 - 13:05  |  Presenting Author(s): Mark A Socinski

      • Abstract

      Abstract not provided

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      Histological and molecular profiling (ID 14852)

      13:05 - 13:20  |  Presenting Author(s): Keith M Kerr

      • Abstract

      Abstract not provided

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      Optimal sequencing of therapy for non-driver lung cancer: chemotherapy + immunotherapy (ID 14853)

      13:20 - 13:40  |  Presenting Author(s): Penelope Bradbury

      • Abstract

      Abstract not provided

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      Optimal sequencing of therapy for non-driver lung cancer: chemotherapy + anti-angiogenics (ID 14854)

      13:40 - 14:00  |  Presenting Author(s): James Chih-Hsin Yang

      • Abstract

      Abstract not provided

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      Identifying and treating patients with refractory or aggressive lung cancer (ID 14855)

      14:00 - 14:20  |  Presenting Author(s): Corey J Langer

      • Abstract

      Abstract not provided

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      Faculty discussion and audience questions (ID 14856)

      14:20 - 14:30  |  Presenting Author(s): Mark A Socinski, Keith M Kerr, Penelope Bradbury, James Chih-Hsin Yang, Corey J Langer

      • Abstract

      Abstract not provided

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    ISS06 - Symposium Supported by Medscape: NTRK Fusions in NSCLC - Practice Changing in 2018 and Beyond? (Not IASLC CME Accredited) (ID 859)

    • Event: WCLC 2018
    • Type: Industry Supported Symposia
    • Track:
    • Presentations: 5
    • Moderators:
    • Coordinates: 9/24/2018, 07:00 - 08:00, Room 106
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      Welcome and Introductions (ID 12161)

      07:00 - 07:05  |  Presenting Author(s): Ramaswamy Govindan

      • Abstract

      Abstract not provided

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      A Case Example of Lung Cancer and NTRK Fusions: Making the Diagnosis (ID 14799)

      07:05 - 07:20  |  Presenting Author(s): Luis E Raez

      • Abstract

      Abstract not provided

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      A Case Example of Lung Cancer and NTRK Fusions: Management (ID 14800)

      07:20 - 07:35  |  Presenting Author(s): Alexander Drilon

      • Abstract

      Abstract not provided

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      Sizing up Resistance: Getting in Front of the Problem (ID 14801)

      07:35 - 07:45  |  Presenting Author(s): Trever G Bivona

      • Abstract

      Abstract not provided

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      Personalizing Therapy in Patients With NTRK Fusions: Will It Go the Way of EGFR? (ID 14802)

      07:45 - 07:50  |  Author(s): Ramaswamy Govindan

      • Abstract

      Abstract not provided

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    ISS10 - Symposium Supported by Boehringer Ingelheim: Overcoming Challenges in Thoracic Malignancies: Expert Insights (Not IASLC CME Accredited) (ID 861)

    • Event: WCLC 2018
    • Type: Industry Supported Symposia
    • Track:
    • Presentations: 6
    • Moderators:
    • Coordinates: 9/24/2018, 18:00 - 19:30, Room 106
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      Meeting Welcome and Introductions (ID 12164)

      18:00 - 18:05  |  Presenting Author(s): David R. Gandara

      • Abstract

      Abstract not provided

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      Clinical considerations in EGFR mutation–positive NSCLC: does treatment sequence matter? (ID 14857)

      18:05 - 18:20  |  Presenting Author(s): Barbara Melosky

      • Abstract

      Abstract not provided

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      Clinical considerations in EGFR mutation–positive NSCLC: the challenge of preventing and managing brain metastases (ID 14858)

      18:20 - 18:35  |  Presenting Author(s): Noemi Reguart

      • Abstract

      Abstract not provided

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      Panel discussion: treatment considerations in adenocarcinoma (ID 14859)

      18:35 - 18:50  |  Presenting Author(s): David R. Gandara, Barbara Melosky, Noemi Reguart

      • Abstract

      Abstract not provided

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      Maximising the clinical potential of TKIs for patients with squamous NSCLC (ID 14860)

      18:50 - 19:10  |  Presenting Author(s): David R. Gandara

      • Abstract

      Abstract not provided

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      Panel discussion: treatment considerations in SqCC of the lung (ID 14861)

      19:10 - 19:25  |  Presenting Author(s): David R. Gandara, Barbara Melosky, Noemi Reguart

      • Abstract

      Abstract not provided

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    ISS12 - Symposium Supported by Roche: Selecting the Right Cancer Immunotherapy Regimen for the Right Patient in First-line Lung Cancer (Not IASLC CME Accredited) (ID 862)

    • Event: WCLC 2018
    • Type: Industry Supported Symposia
    • Track:
    • Presentations: 3
    • Moderators:
    • Coordinates: 9/25/2018, 07:00 - 08:00, Room 106
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      Spotlight on cancer immunotherapy: scientific advances and evolving clinical practice in first-line lung cancer (ID 12165)

      07:00 - 07:00  |  Author(s): Suresh S. Ramalingam

      • Abstract

      Abstract not provided

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      Optimising treatment for first-line NSCLC (ID 14817)

      07:00 - 07:00  |  Presenting Author(s): Vassiliki A Papadimitrakopoulou  |  Author(s): Ross Soo

      • Abstract

      Abstract not provided

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      Putting it all into perspective: what does this mean for our patients? (ID 14818)

      07:00 - 07:00  |  Presenting Author(s): Suresh S. Ramalingam, Vassiliki A Papadimitrakopoulou, Ross Soo

      • Abstract

      Abstract not provided

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    ISS15 - Symposium Supported by AstraZeneca: Stage III NSCLC: Combining Immunotherapies with Standard Treatments… Who, When, Why? (Not IASLC CME Accredited) (ID 866)

    • Event: WCLC 2018
    • Type: Industry Supported Symposia
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 18:00 - 19:30, Room 106
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    MS02 - The Future of IO (ID 781)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Immunooncology
    • Presentations: 5
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 106
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      MS02.01 - What Is/Will Be the Optimal Duration of Therapy with IO? (Now Available) (ID 11405)

      10:30 - 10:45  |  Presenting Author(s): David R. Spigel

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS02.02 - Combination Therapies: Where Are We in 2018? (Now Available) (ID 11406)

      10:45 - 11:00  |  Presenting Author(s): Martin Reck

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS02.03 - Next Generation IO in Lung Cancer (Now Available) (ID 11407)

      11:00 - 11:15  |  Presenting Author(s): Solange Peters

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS02.04 - Optimizing Clinical Trial Designs in Immunotherapy (Now Available) (ID 11408)

      11:15 - 11:30  |  Presenting Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Abstract

      Anti-PD (L)1 therapy is part of the standard of care approaches in 1st line and 2nd line therapy for NSCLC either as monotherapy (1) or in combination with chemotherapy (2) and has shown benefit for a subset of NSCLC defined as tumors with high tumor mutation burden (TMB) in combination with anti-CTLA4 therapy (3).

      Several questions remain though about how to optimally integrate immunotherapy in the standard of care setting. These include questions on the optimal biomarker testing, questions on whether immunotherapy should be sequenced with chemotherapy, optimal duration of therapy and the role of maintenance therapy and finally and most importantly evaluation of novel regimens for tumors that either refractory to immunotherapy or acquire resistance.

      Clinical trials with targeted therapy have demonstrated the power of biomarker integration in clinical trial design in settings where a matched driver mutation and a targeted therapy addressing that mutation is used. It is therefore envisioned that as novel biology emerges we will be able to characterize tumors and their microenvironment and define subsets that would be predicted to benefit from rational combinations. New trial design mandates partitioning patients into more select, precise populations, and identification of these unique groups requires clinical trials to evolve quickly to provide clinically relevant outcomes

      Therefore clinical trial designs that are envisioned to accelerate knowledge and expand the benefit to larger patient populations include:a)clinical trials in early NSCLC-neoadjuvant therapy providing the advantage of obtaining surgical specimens for biological correlates and potentially enhancing the cure rates b)Biopsy driven-clinical trials where biopsies are obtained pre and on therapy and possibly at progression to characterize biologic correlates of response or resistance c) umbrella clinical trials which allow for simultaneous enrollment of several subsets of patients and allocation to appropriate therapies. This latter category allows for modular designs with ineffective agents being replaced by more potent agents based on smaller signal-seeking studies. This paradigm is well represented by the LUNG-MAP (SWOG S1400) study using a multidrug, targeted screening approach to match patients in one of multiple trial substudies, each testing a different drug. This study, has recently incorporated a major focus for immunotherapy-resistant tumors and a new platform has been integrated in this public-private collaboration between the National Cancer Institute, academic institutions, and private industry (4). For the design of randomized phase III studies using overall survival (OS) as the primary endpoint, there is a shift from the conventional approach based on a proportional hazards model to those that account for the unique survival kinetics observed in immuno-oncology trials, such as long-term survival and delayed clinical effect.

      References

      1.Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28. doi: 10.1056/NEJMoa1501824. Epub 2015 Apr 19.

      2. Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer.N Engl J Med. 2018 May 31;378(22):2078-2092. doi: 10.1056/NEJMoa1801005. Epub 2018 Apr 16.

      3. Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden.

      N Engl J Med. 2018 May 31;378(22):2093-2104. doi: 10.1056/NEJMoa1801946. Epub 2018 Apr 16.

      4. LUNG-MAP. lung-map.org/about-lung-map. Accessed June 17, 2018

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      MS02.05 - Convincing Policy Makers to Afford Immunotherapy (Now Available) (ID 11409)

      11:30 - 11:45  |  Presenting Author(s): Carlos Gil Ferreira

      • Abstract
      • Presentation
      • Slides

      Abstract

      Immunotherapy has revolutionized the field of oncology in an increasing number of tumor indications [1]. The challenge is how to incorporate these into the toolbox of medical oncologists, given the complexity and inequities of the distinct healthcare system throughout the globe, limiting financial resources and numerous health needs. Here we provide a series of recommendations that are likely to improve access and reduce the cost of these medications. Nonetheless, there are numerous challenges that must be overcome if the entire cancer population eligible to receive immunotherapy is to benefit from this remarkable advancement in health care.

      In the last 15 years cancer drugs prices have been escalating and have become an issue for patients and the entire healthcare system. Earlier to 2000, the average price for a year of therapy or total treatment was less than $10,000. By 2012, this had increased tenfold, with 92% of the new drugs approved for cancer indications that year costing more than $100,000 per year of treatment. Globally, the costs of oncology therapeutics and supportive care increased 11.5% from 2010 to 2015 [2]. Predictions that integrate trends in incidence, survival, oncology practice patterns, and cost of cancer therapeutics estimate that the total cost of cancer care in the U.S. will rise to $173 billion in 2020 [3].

      Under the present system, drug manufacturers regulate pricing. The rapid approval of new immuno-oncology (I-O) agents, all of which carry substantial price tags, has pulled this issue clearly into view, since payers are key stakeholders in determining coverage and reimbursement for this treatment. Payers through the world are dealing with how to assess these drugs and determining whether they are worth the cost of making them available to patients [4].

      The growing number of drugs combinations that are already expensive leaves payers even more worried. In a recent investigation done by “Precision for Value”20 payers representing 75 million lives and 10 integrated delivery systems secure were inquired about their concerns around combination immunotherapy regimens. The results were: 33% of respondents said it was either very or extremely important whether an immunotherapy was used as part of a combination treatment; 37% said they were more concerned about a particular combination as opposed to another. Of these, almost 75% said a combination of immunotherapies was more concerning than an immunotherapy-chemotherapy combination; 55% of respondents cited cost as their biggest concern around immunotherapy combinations [5].

      In general payers focus on monitoring the use of this drugs applying severe precertification criteria [4]. Their main argument regards that payers articulates that the population is still not relatively wide-ranging, even if there are incredible response rates with some, and so, at the end, they are paying for all [6]. Solid data on patient selection and health economics aspects of I-O indications are eagerly needed. At this purpose the use of biomarkersappears as a significant therapeutic tool since it could predict the benefit from a specific treatment and consequently may help to reduce the cost of pharmacotherapy by enabling the selection of a drug that will offer greater benefit in a distinct population [7]. In fact, some studies have been showing that the use of biomarkers reduces the cost effectiveness of immuno-oncologic therapy [6]. Moreover, studies that include a biomarker-driven health economics analysis may show a value-based pricing strategy for immune-oncologic drugs [1].

      The discussion on access to costly cancer drugs is global. The cost of a drug could directly influence the access and successively the number of patients treated; increasing the access would enable a growth in both economic and health outcomes for all stakeholders. The value-based delivery and reimbursement in oncology are also a cause for discussion. For instance, should a similar medication have distinctive costs for different indications if the results are not the same? Another pricing indication would constrain pharmaceutical producers to contend on costs and results [1, 7].

      Whether the idea is move from a standard capitalism-based pricing model towards value-based oncology care an innovative model for interface between government, pharmaceutical industry, healthcare providers and society should be set up [7]. Moreover, payers should be committed with the provider community. Clear policies based on the most recent data available must be presented. The challenge may be the speed with which science is advancing and this can in any way hamper the updating of the policies.In addition to payers communicating with oncologists and provider networks, drug manufacturers can keep payers up to date on their products [7].

      Finally, there should be some mechanism for all stakeholders to interact and develop strategies, such as what is occurring in Brazil in the context of the Health Industrial Complex Executive Group and Forum (GECIS [8]). This Forum foster the appreciation and utilization of new technologies in healthcare, including the immuno-oncology area. Furthermore, the greater the number of information and dissemination of knowledge important to recognize, understand and accept the introduction of new therapies, the closer we will be of being able to convince stakeholders and then introduce immuno-oncology drugs in the roll of available treatments.

      REFERENCES

      1. Ferreira CG, et al. Increasing Access to Immuno-Oncology Therapies in Brazil. Journal of Cancer Policy. 2018;(16), June, 1-5pp.

      2. Quintiles IMS Institute. Global Oncology Trend Report a Review of 2015 and Outlook to 2020.http://www.imshealth.com/en/thought-leadership/ quintilesims-institute/reports/global-oncology-trend-report-a-review-of-2015- and-outlook-to-2020. Accessed 16 Dec 2016.

      3. Mariotto AB, et al. Projections of the cost of cancer care in the United States: 2010–2020.J Natl Cancer Inst. 2011;103(2):117–28.

      4. Institute for Clinical Immuno-Oncology (2015). Commentary From the Field: Payers as Key Players in the Access and Availability of Immuno-Oncology Therapy. Retrieved June 24, 2018, from https://accc-iclio.org

      5. Precision for Value (2017). Education, Data Are Needed on Combination Immunotherapies. Specialty Pharmacy News, Volume 14, Number 5.

      6. Institute for Clinical Immuno-Oncology (2015). Communicate Effectively with Immuno-Oncology Payers. Retrieved June 24, 2018, fromhttps://accc-iclio.org

      7. Ferreira CG et al.The Value of Biomarkers in Optimizing the Use of Immuno-oncologic Therapy. Journal of Current Drug Targets (2018). In press.

      8. Unified Health System (SUS). Executive Group of the Health Industrial Complex-GECIS. 15 April 2014. Available at: www.portaldasaude.gov.br

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    MS23 - What's New in Targeted Therapy? (ID 801)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Targeted Therapy
    • Presentations: 5
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 106
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      MS23.01 - Novel Combinations of Targeted Therapies (Now Available) (ID 11496)

      10:30 - 10:45  |  Presenting Author(s): Pasi A Jänne

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS23.02 - Emerging or Rare Targets - Fusions, Mutational Burden Etc (Now Available) (ID 11497)

      10:45 - 11:00  |  Presenting Author(s): Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS23.03 - Management of CNS Mets in the Era of CNS-Penetrant TKIs (Med Onc and Rad Onco Perspectives) (Now Available) (ID 11498)

      11:00 - 11:15  |  Presenting Author(s): Marina Chiara Garassino  |  Author(s): Giulia Galli

      • Abstract
      • Presentation
      • Slides

      Abstract

      Central nervous system metastases (CNSMs) are common in non small cell lung cancer (NSCLC). Their incidence is particularly high in presence of driver mutations (25-30% of EGFR mutated NSCLCs, 30-40% of ALK rearranged NSCLCs). CNSMs are associated with short survival and dismal quality of life [1].

      The treatment of CNSMs has traditionally been a challenge for medical oncologists. In fact, most of cytotoxic drugs do not cross the blood-brain barrier (BBB), rendering it difficult to control disease with medical therapy. An integration with radiotherapy (RT) is usually needed, either stereotactic, in presence of a limited number of small lesions, or whole brain (WBRT), in case of disseminated or large metastases. Surgery is generally considered only for single symptomatic lesions [2].

      The introduction of immune checkpoint inhibitors (ICIs) has not radically changed the therapeutic approach to CNSMs, as most of ICIs have a limited intra-cranial activity due to high molecular weight. Potential synergy between ICIs and RT, based on BBB permealization and antigen unmasking, is object of debate [3].

      The major advances have been observed in the field of NSCLC with “druggable” genetic alterations. Recent years have seen the development of many tyrosine kinase inhibitors (TKIs) against EGFR mutations and ALK rearrangements, which are active against a wider range of molecular alterations and often show a significant intra-cranial activity.

      Clinical trials with first and second generation EGFR TKIs (gefitinib, erlotinib, afatinib) showed that their intra-cranial concentration is negligible. As a consequence, brain is the most common site of treatment failure [4].

      Third generation EGFR TKI osimertinib completely changed the perspective. A pooled analyses of patients with CNSMs enrolled in phase II trials showed an intra-cranial objective response rate (IC-ORR) of 54% and a disease control rate (IC-DCR) of 92%, irrespective of RT. Median time to brain progression (B-TTP) was not reached. Brain response was rapid, being evidenced at first evaluation in 80% of patients. A phase I trial investigated the activity and safety of osimertinib 160 mg qd (instead of 80 mg qd) in patients with brain and/or leptomeningeal disease, showing promising activity and manageable toxicity [5].

      First generation ALK TKI crizotinib proved some intra-cranial activity in regulatory trials. However, brain disease control was better in case of previous RT (IC-ORR 33% vs 18%; IC-DCR 62% vs 56%; TTP 13 vs 7 months) [6]

      Ceritinib, the oldest second generation ALK TKI, showed a superior activity on CNSMs (IC-ORR 63% and IC-DCR 63% in ALK-inhibitor-naïve patients). Most of the cases had previously received RT and that the outcome of the remaining patients has not been separately analyzed. However, this result is consistent with the preclinical evidence that ceritinib is transported across the BBB by specific carriers. The ongoing trial ASCEND-7 is addressing the efficacy of ceritinib in a population of patients with brain and/or leptomeningeal disease [7].

      Alectinib, another second generation ALK TKI, has an even higher BBB penetration, with a linear correlation between plasma and brain concentrations. After encouraging data from phase I and II trials, the phase III study ALEX demonstrated a higher IC-ORR for alectinib than for crizotinib in first line (59% vs 26%), with an evident benefit in terms of complete responses (45% vs 9%). About 2/3 of the patients had received RT, but the proportion was balanced between treatment arms [8].

      A higher intra-cranial activity has emerged for brigatinib, one of the newest ALK TKIs. A pooled analyses from 2 clinical trials in both crizotinib-treated and -naïve patients showed an IC-ORR of 46% with 90 mg qd and 67% with 180 mg qd. Median B-TTP was 18.4 months in this last cohort. Interestingly, IC-DCR with brigatinib did not differ according to RT [9].

      Lorlatinib, the last ALK inhibitor, has a broader spectrum of activity on ALK alterations. In a phase I trial on heavily pre-treated patients, IC-ORR was 42%, with 17% of complete responses. Spinal punctures showed that drug concentration in cerebrospinal fluid is 75% of the plasmatic one [10].

      In conclusion, new TKIs have deeply changed the management of CNSMs from NSCLC with driver mutations. Thanks to their intra-cranial activity, rapid and durable brain responses can be seen without RT. The omission of RT allows patients to be spared by the cognitive impairment associated to radiations. Indeed, the optimal tolerability of these molecules favours their upfront administration to patients with CNSMs.

      [1] Rangachari D, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Can 2015; 88(1):108-111.

      [2] Tsao MN, et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): an American Society for Radiation Oncology evidence-based guideline. Pract Rad Oncol 2012; 2:210-215.

      [3] Chajona E, et al. The synergistic effect of radiotherapy and immunotherapy: a promising but not simple partnership. Crit Rev Oncol Hematol 2017; 111:124-132.

      [4] Park SJ, et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer 2012; 77:556–560.

      [5] Goss G, et al. CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. Ann Oncol 2018; 29:687–693.

      [6] Lei YY, et al. Clinical efficacy of crizotinib in Chinese patients with ALK-positive non-small-cell lung cancer with brain metastases. J Thor Disease 2015; 7(7):1181-1188.

      [7] Landi L, Cappuzzo F. Ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer. Exp Rev Pharm Oncol 2016; 9(2):203-214.

      [8] Gadgeel SM, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol 2014; 15(10):1119–1128.

      [9] Camidge DR, et al. Exploratory analysis of brigatinib activity in patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer and brain metastases in two clinical trials. J Clin Oncol 2018; DOI: 10.1200/JCO.2017.77.5841.

      [10] Shaw AT, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol 2017; 18:1590-99.

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      MS23.04 - Targeting Driver Oncogenes in Stage 1-3 NSCLC (Now Available) (ID 11499)

      11:15 - 11:30  |  Presenting Author(s): Helena Yu

      • Abstract
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      Abstract not provided

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      MS23.05 - Role of Immunotherapy in Patients with Molecular Driven NSCLC (Now Available) (ID 11500)

      11:30 - 11:45  |  Presenting Author(s): Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS28 - IO Combinations in Advanced NSCLC (ID 806)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Immunooncology
    • Presentations: 5
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 106
    • +

      MS28.01 - Understanding the Rationale for Combining IO Agents (Now Available) (ID 11520)

      13:30 - 13:45  |  Presenting Author(s): Edward B Garon

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS28.02 - Combination IO+IO (Now Available) (ID 11521)

      13:45 - 14:00  |  Presenting Author(s): Myung-Ju Ahn

      • Abstract
      • Presentation
      • Slides

      Abstract

      Immune checkpoint inhibitors (CPIs) such as anti-cytotoxic T lymphocyte antigen-4 (CTLA-4), anti-programmed death-1 (PD-1), or PD-L1 demonstrated durable response rates across broad range of solid tumors including non-small cell lung cancer (NSCLC), which has revolutionized treatment of solid tumors. In NSCLC, Pembrolizumab monotherapy in patients with high PD-L1 expression showed significant improvement of overall survival (OS) compared with platinum doublets as first-line therapy. For further improvement of efficacy and durable response, several randomized phase III studies of CPIs combined with chemotherapy also demonstrated significant improvement of OS regardless of PD-L1 expression. Given that combination of CTLA-4 inhibitor, ipilimumab with anti-PD1, nivolumab led to significant increase of response rate and survival in malignant melanoma, similar approach has been applied to the treatment of NSCLC. The Checkmate 227 study, a randomized phase 3 trial comparing nivolumab plus ipilimumab (Ipi-Nivo) with standard platinum-based chemotherapy in NSCLC has been conducted. Preplanned co-primary analysis demonstrated significant improvement of progression free survival (PFS) with nivolumab plus ipilimumab in patients with high tumor mutation burden (TMB) of at least 10 mutations per megabase, tested by FoundationOne CDx assay. The median PFS was 7.2 months (95% CI 5.5 to 13.2) versus 5.5 months (HR 0.58, 95% CI 4.4 to 5.8, p<0.001). The objective response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy. The incidence of grade 3 or 4 treatment related adverse events was similar between two arms (31.2% with nivolumab plus ipilimumab vs 36.1% with chemotherapy), however, the incidence of discontinuation of drugs is more common in nivolumab plus ipilimumab combination (17% vs 9%). Although overall survival data are not yet mature, these results indicate that TMB is considered an independent predictive marker for selected patients who most likely benefit from the combination of nivolumab and ipilimumab. Recent update of CheckMate 227 study (Part 2) in patients with < 1% of PD-L1 expression was presented. The PFS was significantly improved with combination of nivolumab plus ipilimumab compared with chemotherapy alone (HR=0.74, 95% CI;0.58-0.94), but the benefit from nivolumab plus ipilimumab combination was confined only in patients with TMB 10 mut/Mb suggesting TMB can be considered predictive biomarker for combination of nivolumab plus ipilimumab. In contrast, the MYSTIC study, which compared durvalumab plus tremelimumab with platinum-based chemotherapy, did not meet the primary endpoint of PFS. Final analysis of overall survival is pending. Actually, achievement of 45% of PFS at 1 yr in patients with <1% of PD-L1 expression with combination of nivolumab plus ipilimumab is quite encouraging. However, several issues still remain for use of TMB as a biomarker in clinical practice. TMB can be analyzed by whole exome sequencing, targeted sequencing from tissue or liquid biopsy, where the study platforms are not standardized. Further, the cut-off value of high TMB is quite variable among studies. The tissue availability for TBM test might be another issue and turn-around time also should be improved.

      Immune checkpoints are orchestrated by a set of co-stimulatory and co-inhibitory molecules that regulate the activation and effector functions of T lymphocytes. Until now, combination of ipilimumab with nivolumab showed promising results in NSCLC, but other combination approach of anti-PD1 or anti-PD-L1 with antibodies targeting other co-inhibitory molecules, such TIM-3, BTLA, VISTA, LAG-3, or TIGIT is actively involved in early clinical trial. Similarly, antibodies targeting co-inhibitory molecules, such CD28, OX40, GITR, CD137 or CD27 combined with anti-PD1 or anti-PDL1 are also underway for early clinical trial (Table 1). Most of these combinational approaches have demonstrated synergistic effect in preclinical model, however, it should be further investigated whether these results can be translated into clinical trial, even though several early clinical studies of combination showed tolerable safety profile and response even CPIs refractory patients. Further, it will be long way to go to determine which combination is the most effective among others. Moreover, continuous efforts to search for predictive biomarker for combination approach of CPIs should be elaborated.

      References

      Hellmann, M.D., et al., Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med, 2018

      Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 2012. 12(4): p. 252-64

      Borghaei H., et al. Nivolumab (Nivo) + platinum-doublet chemotherapy (Chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer with <1% tumor PD-L1 expression: Results from CheckMate 227. J Clin Oncol 36,2018 (suppl;abstr 9001)

      Table 1. Ongoing early clinical trials of co-stimulatory of co-inhibitory molecules alone or in combination with anti-PD1 or anti-PD-L1.

      Molecules

      Agents (Company)

      ClinicalTrials.gov identifier

      Co-inhibitory molecules

      CTLA-4

      Ipilimumab (BMS)

      Tremelimumab (AZ)

      MK1308 (Merck)

      Phase III

      Phase III

      NCT03179436

      TIM3-

      MGB453 (Novartis)

      TSR-022 (Tesaro)

      LY3321367 (Lilly)

      NCT02608268

      NCT02817633

      NCT03099109

      VISTA

      JNJ-61610588 (Janssen) *

      NCT02671955

      LAG-3

      BMS986016 (BMS)

      IMP321 (Primo BioMed)

      LAG525 (Novartis)

      TSR033 (Tesaro)

      MGD013 (MacroGenics)

      NCT02966548

      NCT02614833

      NCT03365791

      NCT03250832

      NCT03219268

      TIGIT

      BMS986207 (BMS)

      OMP313M32 (OncoMed)

      MITIG7192A (Genentech)

      MK7684 (Merck)

      NCT02913313

      NCT03119428

      NCT02794571

      NCT02964013

      Co-stimulatory molecules

      OX40

      GSK3174998 (GSK)

      MOXR0916 (Genentech)

      MEDI0562 (Medimmune)

      PF-04518600 (Pfizer)

      NCT02528357

      NCT02219724

      NCT02318394

      NCT02315066

      GITR

      TRX518 (Leap Therapeutics)

      MEDI1873 (Medimmune)

      BMS986156 (BMS)

      NCT01239134

      NCT02583165

      NCT02598960

      CD137

      Urelumab (BMS)

      Utolimumab (Pfizer)

      NCT01471210

      NCT01307267

      CD27

      Varilumab (Celidex Therapeutics)

      NCT01460134

      *terminated

      e353dbe42c8654f33588d4da0b517469

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      MS28.03 - Combinatorial IO + Chemo (Now Available) (ID 11522)

      14:00 - 14:15  |  Presenting Author(s): Rosalyn Juergens

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS28.04 - Combination with Targeted Therapies (Now Available) (ID 11523)

      14:15 - 14:30  |  Presenting Author(s): Ross Soo

      • Abstract
      • Presentation
      • Slides

      Abstract

      Molecular targeted therapy and immunotherapy have transformed the treatment of lung cancer. In oncogene driven lung cancer such as EGFR mutant or EML4-ALK rearranged NSCLC, molecular targeted therapy is associated with high response rates but are usually not durable. Lately, the use of immune checkpoint inhibitors targeting programmed death receptor-1 (PD-1) and programmed death receptor ligand-1 (PD-L1) have generated regulatory approvals in the first line and pre-treated setting for advanced NSCLC. Single agent immune checkpoint inhibitors are associated with lower responses but responses are more durable. The combination of targeted therapy and immunotherapy can potentially deliver new opportunities to improve anti-cancer treatments. In this presentation, PD1/PD-L1 inhibitors in combination with targeted therapies will be discussed with a focus on EGFR mutant/ ALK rearranged NSCLC. The areas to be reviewed include: (1) oncogene signalling pathways and PD-L1 expression, (2) the reduced effectiveness of immune checkpoint inhibitors in pre-treated EGFR/ALK +ve NSCLC, (3) mechanisms for an impaired response to immune checkpoint inhibitors, (4) the relationship between PD-L1 expression and response to targeted therapy, (5) the immunological effects of molecular targeted therapy and (6) the efficacy and toxicity outcomes in studies of combination targeted therapy and immune checkpoint inhibitors in oncogene driven tumors.

      In addition, the role of immunotherapy in combination with antiangiogenic agents and EGFR monoclonal antibodies in oncogene negative NSCLC will also be presented. A better understanding of the integration of targeted therapies with immunotherapies will be required to inform on the design of combination strategies and improve outcomes and reduce toxicities in patients.

      e353dbe42c8654f33588d4da0b517469

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      MS28.05 - Combining IO with Radiation (Now Available) (ID 11524)

      14:30 - 14:45  |  Presenting Author(s): Corinne Faivre-Finn

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer remains the leading cause of cancer-related death worldwide, with non-small cell lung cancer accounting for 85% of the disease. Over 70% of patients present with locally advanced, non-resectable or metastatic disease and despite improvements in chemo-radiotherapy regimens and the development of molecularly targeted agents, 5 year survival rates remain poor, with acquired resistance to novel targeted therapies becoming a growing concern. Currently there remains an unmet need in effectively treating and inducing durable responses in advanced disease. Targeting the immune system has, however, recently given hope of improving therapeutic outcomes for these patients. The notion that the immune system is capable of recognising and eliminating cancer cells is now a widely accepted phenomenon and growing evidence suggests lung cancer is an attractive target for such intervention. Recent success targeting the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis of immune checkpoint inhibition in stage IV non-small cell lung cancer suggests a major immunotherapeutic advance in treating lung cancer and unheralded opportunity for such approaches to further improve outcome for patients.

      Currently there is considerable interest in combining anti-PD-1 or PD-L1 monoclonal antibodies with established standard of care therapies such as radiotherapy.

      Radiotherapy is known to be immunostimulatory and efforts are underway to combine and augment the efficacy of the immune checkpoint inhibitors further. The combination of radiotherapy with immunotherapy has the potential to augment anti-tumour immune responses. This talk will outline the interaction between lung cancer and the immune system, summarises current evidence supporting the use of monoclonal antibodies targeting the PD-1 axis in lung cancer (including the PACIFIC trial) and will summarise ongoing clinical trials.

      e353dbe42c8654f33588d4da0b517469

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    OA05 - Clinical Trials in IO (ID 899)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 8
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 106
    • +

      OA05.01 - Efficacy/Safety of Entinostat (ENT) and Pembrolizumab (PEMBRO) in NSCLC Patients Previously Treated with Anti-PD-(L)1 Therapy (Now Available) (ID 12922)

      13:30 - 13:40  |  Presenting Author(s): Matthew D. Hellmann  |  Author(s): Pasi A Jänne, Mateusz Opyrchal, Navid Hafez, Luis E Raez, Dmitry Gabrilovich, Fang Wang, Peter Ordentlich, Susan Brouwer, Serap Sankoh, Emmett Schmidt, Michael L Meyers, Suresh S. Ramalingam

      • Abstract
      • Presentation
      • Slides

      Background

      Treatment options are limited for lung cancer patients whose disease has progressed on anti-PD-(L)1 therapy. HDAC inhibitors may synergize with PD-(L)1 inhibition to overcome resistance. We report the interim results of a Phase 2 trial of entinostat (ENT), a class I selective histone deacetylase (HDAC) inhibitor, plus pembrolizumab (PEMBRO) in patients with NSCLC previously treated with anti-PD-(L)1 therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      ENCORE-601 is an open-label study evaluating the combination of ENT + PEMBRO in patients with recurrent or metastatic NSCLC and prior progression on anti-PD-1/PD-L1 therapy. Patients were eligible irrespective of histology or baseline PD-L1 expression. Patients were treated with ENT 5 mg PO weekly and PEMBRO 200 mg IV Q3W. The primary endpoint was ORR as assessed by irRECIST. Tumor biopsies and blood samples for immune correlates were taken prior to and during treatment in a subset of patients. A total of 70 patients will be enrolled.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 57 patients with anti-PD-(L)1 resistant/refractory NSCLC, the confirmed objective response rate with ENT + PEMBRO was 11% (6 of 57, 95% CI: 4-21%). Of 49 patients with post-baseline tumor measurements, 47% had at least some reduction in tumor. Anti-PD-(L)1 therapy was the most recent line of therapy in 38 of 57 patients, and the median time from last dose of prior anti-PD-(L)1 to study entry was 67 days. The median duration of response with ENT + PEMBRO was 5 months, with the longest over 14 months. Of the 6 responders, four were PD-L1 negative at study entry. Response was associated with a higher median baseline level of peripheral classical monocytes (CD14+CD16-HLA-DRhi) with 16.9% of total live PBMCs in responders (n=6) compared to 8.2% in non-responders (n=45). 5 patients (8.8%) experienced Grade 3/4 related irAEs (2 events each of pneumonitis and colitis, 1 event of hyperthyroidism). In addition, 19 patients (33.3%) experienced other Grade 3/4 related AEs with only fatigue, anemia, hypophosphatemia, and hyponatremia occurring in more than 1 patient. Additional correlative analyses to identify biomarkers of response, including whole exome sequencing and RNAseq, are in progress.

      8eea62084ca7e541d918e823422bd82e Conclusion

      ENT + PEMBRO demonstrated anti-tumor activity and acceptable safety in patients with NSCLC who have progressed on prior PD-(L)1 blockade. Ongoing analysis of immune correlates may identify strategies for effective patient selection.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA05.02 - Epacadostat Plus Pembrolizumab in Patients with Non-Small Cell Lung Cancer: Phase 1/2 Results from ECHO-202/KEYNOTE-037 (Now Available) (ID 13535)

      13:40 - 13:50  |  Presenting Author(s): Liza Villaruz  |  Author(s): Bryan J Schneider, Todd M. Bauer, Alexander Spira, Gina D'Amato, Jeffery Wasser, Ani Balmanoukian, Primo Lara, Anthony Olszanski, Thomas Gajewski, Sandip Patel, Ahmad Tarhini, Joshua Michael Bauml, Emmett Schmidt, Jill Bowman, Jeannie Daniel, Sherry Owens, Tara C Mitchell

      • Abstract
      • Presentation
      • Slides

      Background

      Epacadostat (E) is a potent, highly selective inhibitor of the indoleamine 2, 3-dioxygenase 1 (IDO1) enzyme. ECHO-202/KEYNOTE-037 is an open-label, phase 1/2 study of E + pembrolizumab (P) in patients (pts) with advanced tumors (NCT02178722). We report updated efficacy and safety data for the phase 1 and 2 non-small cell lung cancer (NSCLC) cohort as of 8 Jan 2018 data cutoff.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Adult pts with prior platinum-based therapy (tx), no prior immune checkpoint inhibitors, and those intolerant to EGFR-targeted therapy were eligible. Pts could receive E (25, 50, 100, or 300 mg twice daily [BID]) + P (2 mg/kg or 200 mg every 3 weeks [Q3W]) during phase 1; maximum tolerated dose was not achieved. E (100 mg BID) + P (200 mg Q3W) tx doses were selected for phase 2 evaluation. Efficacy was assessed by RECIST v1.1 criteria. Programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) was evaluated using the 22C3 pharmDx assay. IDO1 status was measured by RNAScope. Safety was assessed in pts receiving ≥1 E + P dose.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 70 pts (phase 1, n=12; phase 2, n=58) were evaluated. Median age was 63 years and 57% of pts were female. EGFR mutation status (+/-/not available) was 10%/71%/19%; KRAS status was 19%/26%/56%, respectively. Most pts had adenocarcinoma (70%), a history of smoking (76%), and 0–1 prior lines of tx (64%). PD-L1 TPS results were available in 55/70 pts; IDO1 status (+/-) in 41/70 pts. Overall, the objective response rate (ORR; complete response [CR] + partial response [PR]) and disease control rate (CR + PR + stable disease [SD]) were 29% (20/70; 17 PR) and 50% (35/70; 15 SD), respectively. ORR was 22% (2/9) in pts with TPS ≥50% and 0–1 prior tx; for pts with TPS <50% and 0–1 prior tx, ORR was 22% (5/23). ORR for pts with IDO1+ and IDO1- tumors were 24% (6/25) and 19% (3/16), respectively. At data cutoff, 10/20 responses were ongoing. Median progression-free survival (PFS) was 4.0 mo (90% confidence interval, 2.1–6.2 mo); PFS rates at 6, 12, and 18 mo were 43% (33%–53%), 31% (22%–40%), and 17% (10%–26%), respectively. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 27% of pts; 3 pts discontinued due to TRAEs; and no TRAEs led to death.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The E + P combination was generally well tolerated and associated with promising responses in pts with NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA05.03 - Safety and Clinical Activity of Adoptive Cell Transfer Using Tumor Infiltrating Lymphocytes (TIL) Combined with Nivolumab in NSCLC (Now Available) (ID 14388)

      13:50 - 14:00  |  Presenting Author(s): Ben C. Creelan  |  Author(s): Jamie K Teer, Eric M Toloza, John E Mullinax, Ana M Landin, Jhanelle Elaine Gray, Tawee T Tanvetyanon, Matthew C Taddeo, David R Noyes, Linda L Kelley, Bin Fang, John M Koomen, Amod A Sarnaik, Sungjune Kim, Eric B. Haura, Scott J Antonia

      • Abstract
      • Presentation
      • Slides

      Background

      Adoptive transfer of tumor infiltrating lymphocytes (TIL) can cause durable regression by recognition of neoantigens unique to the patient. NSCLC TIL has synergistic preclinical activity with nivolumab, and we hypothesized it may induce remissions in anti-PD1-refractory patients. We initiated a phase I trial with the primary objective to characterize the safety and preliminary activity of the combination.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Metastases from patients with Stage 4 NSCLC were resected, morselized, cultured, and tested for autologous reactivity. Reactive TIL fragments were pooled and cryopreserved. Patients received nivolumab over 8 weeks. Patients with progressive disease (PD) proceeded to lymphodepletion cyclophosphamide/fludarabine (Cy/Flu), TIL, and IL-2. Tumor whole exome sequencing, transcriptomics, and LC-MS/MS peptide sequencing was performed. TCR-Vß rearrangements were analyzed from tumor, TIL, and pre-/post-infusion peripheral lymphocytes.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 14 patients enrolled to date, 13 had successful ex vivo TIL expansion from resected metastases. TIL had high proliferative capacity, expanding to median 81 billion CD3+ cells infused per patient (range 27–138 billion) and median 27% of fragments were autologously reactive (range 0-67%). Demographics: median age 54 (range 44-74), median TMB 4 mutations/MB (range 0.9–25), median PD-L1 proportion-score 0% (range 0–100%), and 4 had LKB1 allelic inactivation. Predicted neoantigens correlated with variants on proteomic sequencing. Outcomes: 9 patients had confirmed PD on nivolumab, and proceeded to receive Cy/Flu/TIL/IL-2. No unexpected serious adverse reactions (SUSARs) were identified. Of these 9 patients, 7 had reduction in sum of target lesions at Day+28 CT scan (Figure 1). Peripheral lymphocytes expanded at Days 2-7 in the majority of patients. In patients tested to date, TIL clonotypes persisted through Day+100, and CCR7+CD95+CD45RA+ stem cell-like memory (TSCM) cells were increased at post-infusion timepoints.

      abstract figure.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Adoptive cell transfer with TIL and nivolumab for NSCLC had acceptable toxicity and preliminary activity in this ongoing trial.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA05.04 - Discussant - OA 05.01, OA 05.02, OA 05.03 (ID 14554)

      14:00 - 14:15  |  Presenting Author(s): Scott Owen  |  Author(s): Martin J. Edelman

      • Abstract
      • Slides

      Abstract not provided

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      OA05.05 - Avelumab vs Docetaxel for Previously Treated Advanced NSCLC: Primary Analysis of the Phase 3 JAVELIN Lung 200 Trial (Now Available) (ID 12930)

      14:15 - 14:25  |  Presenting Author(s): Fabrice Barlesi  |  Author(s): Johan F. Vansteenkiste, David R. Spigel, Hidenobu Ishii, Marina Chiara Garassino, Filippo De Marinis, Mustafa Özgüroğlu, Aleksandra Szczesna, Andreas Polychronis, Ruchan Uslu, Maciej Krzakowski, Jong-Seok Lee, Luana Calabro, Osvaldo Arén Frontera, Barbara Ellers-Lenz, Marcis Bajars, Mary Ruisi, Keunchil Park

      • Abstract
      • Presentation
      • Slides

      Background

      Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody that is an approved treatment for metastatic Merkel cell carcinoma (various regions) and platinum-treated advanced urothelial carcinoma (US). We report findings from a global, open-label, phase 3 trial of avelumab vs docetaxel in patients with advanced NSCLC after platinum failure (NCT02395172).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with stage IIIB/IV or recurrent NSCLC with disease progression after platinum doublet therapy were randomized 1:1 to avelumab 10 mg/kg Q2W or docetaxel 75 mg/m2 Q3W, stratified by PD-L1 status (PD-L1+/PD-L1−) and histology (squamous/nonsquamous). The primary endpoint was overall survival (OS) in the PD-L1+ population (expression on ≥1% of tumor cells, assessed using the PD-L1 IHC 73-10 assay).

      4c3880bb027f159e801041b1021e88e8 Result

      Between April 2015 and February 2017, 792 patients were randomized to receive avelumab or docetaxel, including 264 and 265 with PD-L1+ tumors, respectively; 0.8% vs 7.5% did not receive study treatment. Median follow-up in the avelumab and docetaxel arms was 18.9 and 17.8 months; 15.5% vs 1.5% remained on treatment at data cutoff (November 22, 2017). In the avelumab and docetaxel arms, 39.8% vs 47.5% received subsequent anticancer therapy after discontinuation, including checkpoint inhibitors in 5.7% vs 26.4%, respectively. In the PD-L1+ population, median OS in the avelumab and docetaxel arms was 11.4 vs 10.3 months (hazard ratio [HR], 0.90 [96% CI, 0.72-1.12]; P=0.1627, 1-sided). Pre-planned exploratory analyses based on higher PD-L1 cutoffs showed increased OS with avelumab vs docetaxel, including PD-L1-high (≥80% cutoff, 29% of patients; 17.1 vs 9.3 months; HR, 0.59 [95% CI, 0.42-0.83]; P=.0022, 2-sided) and PD-L1-medium/high (≥50% cutoff, 40% of patients; 13.6 vs 9.2 months; HR, 0.67 [95% CI, 0.51-0.89]; P=0.0052, 2-sided) subgroups. In the PD-L1+ population (≥1% cutoff), ORR was 18.9% vs 11.7% (odds ratio, 1.76 [95% CI, 1.08-2.86]; P=0.0105, 1-sided); median duration of response was not reached with avelumab (95% CI, 9.9-not estimable [NE]) vs 6.9 months with docetaxel (95% CI, 3.5-NE). Overall rates of treatment-related adverse events (AEs) were lower with avelumab than docetaxel, including all grades (63.9% vs 85.8%) and grade ≥3 (9.9% vs 49.3%). Immune-related AEs occurred in 16.5% of avelumab-treated patients (grade ≥3 in 2.8%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Avelumab showed increasing clinical activity in patients who had platinum-treated NSCLC with higher tumor PD-L1 expression; however, the trial did not meet its primary objective of improving OS vs docetaxel in PD-L1+ tumors (≥1% cutoff). OS findings may have been confounded by subsequent checkpoint inhibitor therapy in the docetaxel arm.

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      OA05.06 - CheckMate 227: Patient-Reported Outcomes of First-Line Nivolumab + Ipilimumab in High Tumor Mutational Burden Advanced NSCLC (Now Available) (ID 13450)

      14:25 - 14:35  |  Presenting Author(s): Julie R. Brahmer  |  Author(s): Michael Schenker, Ki Hyeong Lee, Mariano Provencio, Makoto Nishio, Krzysztof Lesniewski-Kmak, Randeep Sangha, Samreen Ahmed, Judith Raimbourg, Kynan Feeney, Romain Corre, Fabio Andre Franke, Eduardo Richardet, John R. Penrod, Yong Yuan, Faith Nathan, Prabhu Bhagavatheeswaran, Michael De Rosa, Fiona Taylor, Rachael Lawrance, Martin Reck

      • Abstract
      • Presentation
      • Slides

      Background

      The randomized, open-label, multipart phase 3 study CheckMate 227 (NCT02477826) demonstrated a significant progression-free survival benefit (co-primary endpoint) with first-line nivolumab+ipilimumab versus histology-based, platinum-doublet chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and high tumor mutational burden (TMB; ≥10 mutations/Mb). Patient-reported outcomes (PROs) for this population within CheckMate 227 are presented.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible chemotherapy-naïve patients had stage IV or recurrent NSCLC, ECOG performance status 0−1, and no known sensitizing EGFR/ALK alterations. PROs were assessed as an exploratory endpoint; this analysis included patients with high TMB randomized to nivolumab+ipilimumab or chemotherapy; specific outcomes included proportion of patients with disease-related symptom deterioration by 12 weeks and time to deterioration in symptoms (by Lung Cancer Symptom Scale [LCSS] Average Symptom Burden Index [ASBI]), and assessment of quality of life and overall health status (by EuroQoL-5 Dimension [EQ-5D] utility index [UI] and visual analog scale [VAS]). PROs were evaluated each cycle (Q2W, nivolumab+ipilimumab; Q3W, chemotherapy) for the first 6 months, every 6 weeks thereafter during treatment, and at follow-up visits 1/2. EQ-5D was also assessed during survival follow-up.

      4c3880bb027f159e801041b1021e88e8 Result

      PRO completion rates were ~90% at baseline and >80% for nearly all on-treatment assessments. Among patients with high TMB, fewer patients in the nivolumab+ipilimumab (n=139) versus chemotherapy (n=160) groups reported symptom deterioration by week 12, irrespective of whether they were still on therapy or had discontinued (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% CI: 2.4–22.5]). Time to first deterioration (TTD) using common assessment time points (on/off treatment) was delayed with nivolumab+ipilimumab versus chemotherapy for the LCSS ASBI (hazard ratio [HR]: 0.40; 95% CI: 0.26–0.63) and 3-Item Global Index (3-IGI; HR: 0.56; 95% CI: 0.38–0.82). The estimated benefit in TTD generally favored nivolumab+ipilimumab for individual symptoms in the ASBI and each item in the 3-IGI (HRs: 0.48–0.74), except for hemoptysis (HR: 1.20), which exhibited very low burden; an advantage for nivolumab+ipilimumab was also seen in the EQ-5D VAS (HR: 0.62; 95% CI: 0.42–0.92) and UI (HR: 0.50; 95% CI: 0.34–0.73). Mean changes from baseline with nivolumab+ipilimumab showed early and clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; for patients treated with chemotherapy, symptoms and quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following completion of chemotherapy (EQ-5D VAS).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Nivolumab+ipilimumab demonstrated early and sustained improvements in health-related quality of life versus chemotherapy in patients with advanced NSCLC and high TMB.

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      OA05.07 - IMpower132: PFS and Safety Results with 1L Atezolizumab + Carboplatin/Cisplatin + Pemetrexed in Stage IV Non-Squamous NSCLC (Now Available) (ID 12389)

      14:35 - 14:45  |  Presenting Author(s): Vassiliki A Papadimitrakopoulou  |  Author(s): Manuel Cobo, Rodolfo Bordoni, Pascale Dubray-Longeras, Zsuzsanna Szalai, Grigoriy Ursol, Silvia Novello, Francisco Orlandi, Simon Ball, Jerome Goldschmidt Jr., Rachel E Sanborn, Tien Hoang, Diana Mendus, Yu Deng, Marcin Kowanetz, Xiaohui Wen, Wei Lin, Alan Sandler, Makoto Nishio

      • Abstract
      • Presentation
      • Slides

      Background

      In addition to the combination of atezolizumab (anti–PD-L1)+platinum+taxane±bevacizumab, non-squamous NSCLC patients may derive benefit from adding atezolizumab to platinum+pemetrexed. The randomized Phase III IMpower132 study (NCT02657434) evaluated first-line pemetrexed+carboplatin or cisplatin±atezolizumab in patients with stage IV non-squamous NSCLC without EGFR or ALK driver mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients were randomized 1:1 to receive 4 or 6 cycles of carboplatin AUC 6 mg/mL/min or cisplatin 75 mg/m2 + pemetrexed 500 mg/m2 Q3W alone (arm PP) or in combination with atezolizumab 1200 mg Q3W (arm APP), followed by pemetrexed (arm PP) or atezolizumab + pemetrexed (arm APP) maintenance. Atezolizumab could be continued beyond disease progression per protocol guidelines. PFS and OS were co-primary endpoints. Efficacy by PD-L1 expression was an exploratory endpoint. Here, we present investigator-assessed PFS per RECIST v1.1 (final analysis), OS (interim analysis) and safety data.

      4c3880bb027f159e801041b1021e88e8 Result

      292 pts were enrolled in arm APP and 286 pts in arm PP. 43% and 40% in arms APP and PP, respectively, had ECOG PS 0. At the data cutoff (22 May 2018), median follow-up was 14.8 mo overall. PFS analysis showed a statistically significant improvement between arm APP vs PP (median PFS 7.6 vs 5.2 mo; HR=0.596; 95% CI: 0.494, 0.719; P<0.0001). Interim analysis showed a numerical but non-statistically significant OS improvement (Table). Efficacy results were consistent across all key clinical subgroups. Grade 3-4 TRAEs occurred in 53.6% of patients (APP) vs 39.1% (PP). 7.2% of patients (APP) vs 5.1% (PP) had a Grade 5 AE, 3.8% (APP) vs 2.6% (PP) were treatment related. 48.5% of patients (APP) vs 38.0% (PP) experienced AEs of special interest specific to atezolizumab.

      8eea62084ca7e541d918e823422bd82e Conclusion

      IMpower132 met its co-primary endpoint of investigator-assessed PFS in the ITT. Interim OS data (not fully mature) showed numerical improvement. Atezolizumab+pemetrexed+carboplatin or cisplatin was well tolerated, and no new safety signals were identified.

      Table. IMpower132 Efficacy Analyses

      APP Arm
      (atezolizumab+pemetrexed+ carboplatin or cisplatin)
      PP Arm
      (pemetrexed+carboplatin or cisplatin)
      ITT n=292 n=286
      Median PFS (95% CI), mo 7.6 (6.6, 8.5) 5.2 (4.3, 5.6)
      HRa (95% CI; P value) 0.596 (0.494, 0.719; P < 0.0001)
      12-Month PFS (95% CI), % 33.7% (28.2, 39.2) 17.0% (12.6, 21.4)
      Median OS (95% CI), mo 18.1 (13.0, NE) 13.6 (11.4, 15.5)
      HRa (95% CI; P value) 0.813 (0.644, 1.025; P = 0.0797)
      12-Month OS (95% CI), % 59.6% (53.9, 65.3) 55.4% (49.5, 61.2)
      ORR (confirmed, inv-assessed), % 46.9% 32.2%
      DOR (95% CI), mo 10.1 (7.2, 13.3) 7.2 (5.7, 9.0)
      PD-L1–highb n=25 n=20
      Median PFS (95% CI), mo 10.8 (7.9, NE) 6.5 (2.4, 10.6)
      HR (95% CI; P value) 0.464 (0.224, 0.960; P = 0.0339)
      PD-L1–lowb n=63 n=73
      Median PFS (95% CI), mo 6.2 (4.4, 8.4) 5.7 (4.2, 7.9)
      HR (95% CI; P value) 0.804 (0.556, 1.163; P = 0.2462)
      PD-L1–negativeb n=88 n=75
      Median PFS (95% CI), mo 8.5 (6.1, 11.2) 4.9 (4.2, 5.8)
      HR (95% CI; P value) 0.448 (0.313, 0.642; P < 0.0001)

      DOR, duration of response; HR, hazard ratio; inv, investigator; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

      a Stratified. b Baseline tissue available in 60% of patients. PD-L1high (TC3/IC3): patients with PD-L1 expression in ≥50% of tumor cells or ≥10% of tumor-infiltrating immune cells; PD-L1low (TC12/IC12): patients with PD-L1 expression in ≥1% and <50% of tumor cells or ≥1% and <10% of tumor-infiltrating immune cells; and PD-L1negative (TC0/IC0): patients with PD-L1 expression in <1% of tumor cells and <1% of tumor-infiltrating immune cells.

      NCT02657434

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      OA05.08 - Discussant - OA 05.05, OA 05.06, OA 05.07 (Now Available) (ID 14555)

      14:45 - 15:00  |  Presenting Author(s): Hossein Borghaei

      • Abstract
      • Presentation
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      Abstract not provided

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    OA10 - Right Patient, Right Target & Right Drug - Novel Treatments and Research Partnerships (ID 910)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 8
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 106
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      OA10.01 - Patient Preferences for Tyrosine Kinase Inhibitor Treatments for EGFR Mutation Positive Metastatic NSCLC (Now Available) (ID 13735)

      10:30 - 10:40  |  Presenting Author(s): John F.P. Bridges  |  Author(s): Marie De La Cruz, Melissa Pavilack, Emuella Flood, Ellen Janssen, Nabil Chehab, Ancilla W. Fernandes

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR mutation positive (EGFRm) NSCLC responds to EGFR-tyrosine kinase inhibitors (TKIs). First-, second-, and third-generation EGFR-TKI treatment attributes vary in efficacy, side effects, and dosing regimen. We used two different methods to explore treatment preferences among patients with EGFRm metastatic NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with EGFRm metastatic NSCLC were recruited in the US to participate in an online survey containing two complimentary preference elicitation methods. First, preferences were assessed through direct elicitation exercises where participants chose between competing treatment profiles. The first exercise compared two profiles with a large difference in progression-free survival (PFS) (6 vs 18 months). The second exercise compared two profiles with a smaller difference (10 vs 18 months). Both exercises compared the same side effect risks (0–1% vs 2–16% risk). Second, a discrete choice experiment (DCE) was used to assess preferences for variation in treatments in terms of PFS, severity of side effects (mild/moderate/severe), and mode of administration. These attributes and levels were varied based on a D-efficient design. Participants completed 10 DCE choice tasks where they saw pairs of hypothetical treatments with different attribute levels and selected their preferred treatment. A choice model was estimated using conditional logit regression.

      4c3880bb027f159e801041b1021e88e8 Result

      Between 10/2017 and 03/2018, 90 patients with EGFRm metastatic NSCLC were recruited and completed the survey: 42% female; 79% white; 76% taking first-line or second-line EGFR-TKIs at time of survey. Median time since diagnosis: 2.1 years (inter-quartile range: 1.1–2.7). In the direct elicitation exercise, participants opted for shorter PFS in exchange for more favorable side effects, but were less likely to do so for a large difference in PFS (52% of participants) vs a smaller difference (66%; p<0.001). Participants who chose shorter PFS when difference in PFS was large were more likely to be taking EGFR-TKIs (odds ratio: 21.4; 95% confidence interval: 2.24, 204.88). No relationship between choice and treatment characteristic was observed when difference in PFS was small. In the DCE, conditional logit regression indicated that to avoid severe levels of nausea/vomiting, diarrhea, rash, or fatigue, participants on average would accept reductions in PFS of 13, 11, 9, and 8 months, respectively. Participants would accept reduction in PFS of 7 months for oral treatment taken with/without food vs IV.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this online survey of patients with EGFRm metastatic NSCLC, some patients were willing to accept shorter PFS for a better safety profile and dosing convenience; however, PFS remained an important attribute in treatment choice.

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      OA10.02 - Oncogene-Driven Patient Groups: A New Era For Research Partnerships (Now Available) (ID 13519)

      10:40 - 10:50  |  Presenting Author(s): Janet Freeman-Daily  |  Author(s): Ivy Elkins, Laura Greco, Marcia K Horn, Bonnie Addario, David LeDuc, Robert C. Doebele, Christine Lovly

      • Abstract
      • Presentation
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      Background

      Genomic alterations drive more than 60% of non-small cell lung cancer (NSCLC). About 20% of NSCLC cases (EGFR, ALK, ROS1, BRAF) will have an oncogenic driver that can be treated with approved targeted therapy drugs, and more have clinical trial options. In some cases, patients on targeted therapies will have years of good quality of life. However, targeted therapies do not cure, and these patients will eventually see their cancer progress. Patients and caregivers dealing with cancers driven by EGFR, ALK, ROS1 and Exon20 oncogenes have organized globally into online groups and are building partnerships that seek to provide support, increase awareness and education, accelerate and fund research, and improve access to effective diagnosis and treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Each patient-caregiver group forms using social media, patient blogs, websites, fliers, newsletters, and contacts with clinicians. Each has a private Facebook group or other network to inform and educate patients and caregivers of approved and experimental treatments, share common experiences, provide information and tips from expert clinicians and researchers, and enable real-life connections. Each group sets its own priorities such as creating websites, raising funds for research, donating tissue, developing studies of demographics and treatment sequences, and creating biorepositories with annotated specimens that will be made widely available. These projects are accomplished in patient-driven partnership with researchers, clinicians, advocacy groups, and industry. None of the patient-caregiver groups are corporations or other types of legal entities.

      4c3880bb027f159e801041b1021e88e8 Result

      The ROS1ders focus on ROS1+ cancers of all types and include over 275 members from 21 countries across 8 cancer types. They have partnered in two studies to create ROS1+ cancer models. ALK Positive focuses on ALK+ NSCLC and other cancers, and includes over 1000 members from 38 countries. They have raised nearly $400,000 for research and will announce two grants in May. Exon 20 Group focuses on EGFR and HER2 insertions in Exon 20, and includes 110 members from 19 countries. They created an Exon 20 molecular tumor board and awarded two grants. The EGFR Resisters focus on EGFR+ NSCLC and cancers that develop resistance to EGFR targeted therapies, and include over 450 members from 20 countries.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Oncogene-driven patient-caregiver groups are creating a new paradigm in cancer research and have demonstrated that their partnerships with advocacy organizations, clinicians, researchers and industry, combined with social media outreach, can increase available patient data, specimens, cancer models and research funding for geographically distributed, oncogene-driven cancer populations.

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      OA10.03 - Discussant - OA 10.01, OA 10.02 (Now Available) (ID 14564)

      10:50 - 11:05  |  Presenting Author(s): Zofia Piotrowska

      • Abstract
      • Presentation
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      Abstract not provided

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      OA10.04 - Afatinib With or Without Cetuximab for EGFR-Mutant Non-Small Cell Lung Cancer: Safety and Efficacy Results from SWOG S1403 (Now Available) (ID 14014)

      11:05 - 11:15  |  Presenting Author(s): Sarah B Goldberg  |  Author(s): Mary W. Redman, Rogerio Lilenbaum, Katerina Politi, Thomas E. Stinchcombe, Leora Horn, Everett H. Chen, Sandeep Mashru, Scott N. Gettinger, Mary Ann Melnick, Jieling Miao, James Moon, Karen Kelly, David R. Gandara

      • Abstract
      • Presentation
      • Slides

      Background

      Several EGFR tyrosine kinase inhibitors (TKIs) are used for the treatment of EGFR-mutant non-small cell lung cancer (NSCLC), however resistance inevitably develops. The combination of the irreversible ErbB family TKI afatinib and the EGFR monoclonal antibody cetuximab was previously shown to overcome resistance to first-line EGFR TKIs. To attempt to delay resistance, we conducted a randomized trial of afatinib plus cetuximab versus afatinib alone in treatment-naïve patients with advanced EGFR-mutant NSCLC (NCT02438722).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with previously-untreated EGFR-mutant NSCLC were randomized to afatinib 40mg PO daily plus cetuximab 500mg/m2 IV every 2 weeks or afatinib 40mg PO daily. The study was designed to accrue a total of 212 patients, comparing progression-free survival (PFS) between the arms at the 1-sided 0.025 level when 134 PFS events had been observed. Secondary objectives included comparison of overall survival (OS), time to treatment discontinuation (TTD), and toxicity. An interim analysis evaluating early stopping for futility occurred when at least 64 PFS events were reported.

      4c3880bb027f159e801041b1021e88e8 Result

      Between March 26, 2015 and April 23, 2018, 170 eligible patients were accrued: 86 to afatinib/cetuximab and 84 to afatinib. Median age was 66.4 years, 66% were female, 64% had an EGFR exon 19 deletion mutation and 36% had an L858R point mutation. With 109 events observed, there was no improvement in PFS with the combination compared to single-agent (HR 1.17, 95% CI 0.80-1.73, P = 0.42, median 10.6 months vs 13.1 months). OS was also not improved with the addition of cetuximab (HR 1.23, 95% CI 0.62-2.44, P = 0.55, median 26.9 months vs not reached). TTD was similar between the two groups (HR 0.95, 95% CI 0.64-1.39, P = 0.79, median 12.5 months vs 12.2 months). Grade > 3 treatment-related adverse events (AEs) were more common among patients treated with afatinib/cetuximab, and more patients in the combination arm required at least 1 dose reduction of afatinib (57% vs 26%). However, treatment discontinuations due to AEs were similar between the two groups (11.6% vs 10.7%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      There was no difference in PFS, OS or TTD with the addition of cetuximab to afatinib for treatment-naïve patients with EGFR-mutant NSCLC. The trial was closed to accrual at the interim analysis having met the criteria for futility. Correlative analysis of tumor tissue and blood from patients is ongoing.

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      OA10.05 - An Open-Label, Multicenter, Phase II Single Arm Trial of Osimertinib in NSCLC Patients with Uncommon EGFR Mutation(KCSG-LU15-09) (Now Available) (ID 14365)

      11:15 - 11:25  |  Presenting Author(s): Jang Ho Cho  |  Author(s): Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Keon Uk Park, Eun Joo Kang, Yoon Hee Choi, Ki Hwan Kim, Ho Jung, An An, Hyun Woo Lee, Myung-Ju Ahn

      • Abstract
      • Presentation
      • Slides

      Background

      Approximately 10% of EGFR mutants harbor uncommon mutations, which represent a heterogeneous group of rare molecular alterations within exons 18-21 and the sensitivity to EGFR TKIs is variable. Osimertinib is a potent irreversible inhibitor of both sensitizing EGFR mutation and T790M. In preclinical data, osimertinib was found to be active against most uncommon EGFR mutants, apart from the exon 20 insertion variant. Here we present the efficacy and safety of osimertinib in patients with uncommon EGFR mutation positive NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with histologically confirmed metastatic or recurrent NSCLC with activating EGFR mutation other than exon 19 deletion, L858R, T790M and insertion in exon 20 were eligible. Patients received 80mg of osimertinib orally, once daily until progression or unacceptable toxicity. Response was assessed every 8 weeks by investigator. The trial was registered with ClinicalTrials.gov, number NCT03424759.

      4c3880bb027f159e801041b1021e88e8 Result

      Between Mar 2016 and Oct 2017, 35 patients were enrolled. Median age was 59, 63% male, 43% never smoker, 97% adenocarcinoma. 63% of patients were treated as first-line therapy. The mutations identified were G719A/C/D/S/X (19, 54.3%) followed by L861Q (9, 25.7%), S7681 (8, 22.9%), and others (3, 8.6%). The overall response rate was 50.0% (95% CI 32.8-67.2) and DCR was 88.9% (95% CI 78.1-99.7). Seven patients (77.8%) with L861Q mutation achieved partial response; 10/19 (52.6%) with G719A/C/D/S/X mutation; 3/8 (37.5%) with S768I mutation. At data cutoff (Apr, 2018), the median PFS was 8.2 months (95% CI 1.9- 14.4) and median duration of response was 9.8 months (95% CI 7.6-12.0). The most common adverse events were rash (n=11, 31.4%), anorexia (n=8, 22.9%), and diarrhea (n=7, 20.0%). Grade 3 or 4 AEs were reported in 8 of 35 patients (23%), but all of AEs were manageable.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Osimertinib showed highly active in NSCLC patients harboring uncommon EGFR mutation with manageable safety profile, consistent with previous reports. Further analysis will be provided.

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      OA10.06 - A First-in-Human Phase 1 Trial of the EGFR-cMET Bispecific Antibody JNJ-61186372 in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 13006)

      11:25 - 11:35  |  Presenting Author(s): Keunchil Park  |  Author(s): Myung-Ju Ahn, Se-Hoon Lee, Hye Ryun Kim, Min Hee Hong, Dawn Millington, Martin Curtis, Spyros Triantos, Sandra Chaplan, Nahor Haddish-Berhane, Roland Knoblauch, Zuleima Aguilar, Sylvie Laquerre, Matthew V. Lorenzi, Byoung Chul Cho

      • Abstract
      • Presentation
      • Slides

      Background

      JNJ-61186372 (JNJ-372) is a bispecific antibody targeting both EGFR and cMET. In preclinical studies, JNJ-372 demonstrated efficacy in EGFR and cMET driven tumor xenograft models (including EGFR T790M and MET-amplified/HGF secretion), consistent with inhibition of ligand binding, receptor degradation, and ADCC activity. The goal of Part 1 of this study (reported here) was to assess the safety, pharmacokinetics (PK), and preliminary efficacy of JNJ-372 and to identify the recommended phase 2 dose(s) to be explored in Part 2.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with previously treated, advanced NSCLC were enrolled at two sites and treated with escalating doses of JNJ-372 administered IV weekly for the first 4-week cycle, then biweekly for each subsequent cycle. PK sampling was taken at multiple time points within cycle 1 and 2. Disease assessments were performed every 8 weeks. Tumors were characterized at baseline through next-generation sequencing of circulating tumor DNA (Guardant 360).

      4c3880bb027f159e801041b1021e88e8 Result

      25 patients were treated with JNJ-372 during dose escalation: 140mg (n=3), 350mg (n=3), 700mg (n=9), 1050mg (n=7), 1400mg (n=3). Median age was 63y, 48% were male, 100% were Asian, 84%/12%/4% had adenocarcinoma/squamous/other histology, and median prior therapies was 4. No dose-limiting toxicities were observed at any dose level tested. The most frequent treatment-emergent AEs were infusion-related reactions (76%), rash/acneiform dermatitis (40%), dyspnea (24%), paronychia (24%), pruritus (20%), fatigue (20%), and nausea (20%); incidence of peripheral edema (cMET-related toxicity) was 12%. Infusion-related reactions were grade ≤2 severity, observed primarily with the first dose. The worst severity of rash/acneiform dermatitis was grade 2 (16%). One treatment-related AE of grade ≥3 severity was reported (neutropenia grade 3, possibly related). JNJ-372 demonstrated linear PK at dose levels 350 mg and above with non-linear PK at lower concentrations, suggesting target-mediated drug disposition. Doses ≥700mg resulted in average steady-state concentrations at or above the preclinically established therapeutic target level. Preliminary evidence of efficacy (maximum change from baseline in sum of target lesion diameters) was observed in a patient with squamous cell carcinoma (-20%), a patient with wtEGFR adenocarcinoma (-20%), and 4 patients with EGFR-mutant adenocarcinoma (≥-30%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      JNJ-372 is a novel EGFR-cMET bispecific antibody. The manageable safety profile and preliminary evidence of clinical activity support active accrual of patients with previously treated EGFR-mutant NSCLC. The first recommended dose of 1050mg is being evaluated in Part 2.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA10.07 - Resistance Mechanisms of Osimertinib in Chinese Non-Small Cell Lung Cancer Patients: Analysis from AURA17 Trial (Now Available) (ID 12693)

      11:35 - 11:45  |  Presenting Author(s): Caicun Zhou  |  Author(s): Min Hu, Xuehua Zhu, Yun Sun, Xuesong Lu, Jia Wang, Mengzhao Wang, Ying Cheng, Yuan Chen, Yanqiu Zhao, Yuan-Kai Shi, You Lu, Meiqi Shi, He-Long Zhang, Xiangning Huang, Zheng Wang, Zhijie Ding, Heyan Li, George Chen, Yi-Long Wu

      • Abstract
      • Presentation
      • Slides

      Background

      Osimertinib is approved for metastatic NSCLC patients with EGFR T790M mutation after progression from TKI therapy. Despite impressive tumor responses, drug resistance usually develops. The resistance mechanisms of osimertinib are emerging but studies with large cohorts of Chinese patients and association with clinical outcomes are lacking. Here we report a biomarker study of osimertinib using plasma samples from 107 Chinese patients who had progressed by 24 months after LSFD (Oct. 2017) of AURA17 (NCT02442349), the 2nd-line pivotal trial in China.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Serial plasma cell-free DNA (cfDNA) were collected from baseline until progressive disease (PD) by investigator assessment. Capture-based 75-gene NGS panel with unique molecular index (UMI) system was used to identify resistance mechanisms to osimertinib by comparing paired cfDNA at baseline and PD. Droplet digital PCR (ddPCR) was used to dynamically monitor EGFR mutation changes (L858R, Ex19Del, T790M and C797S) during treatment course. Association of cfDNA biomarkers based on valid test results with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) from DCO3 (Mar. 20, 2018) was analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      The 107 patients were with ORR of 68.2%, median PFS of 8.2 months, and median OS of 21.5 months. Eight-two had detectable EGFR sensitizing mutations (L858R or Ex19Del) in their PD cfDNA samples. Among them, 15 had acquired EGFR C797S, all in cis with T790M, and with no enrichment for L858R or Ex19Del (6 and 9, respectively). The median time of C797S detection from plasma was 2.8 (1.2-8.4) months prior to PD. EGFR L718Q, I744T, C775Y, G796S/D, T854I mutations, or amplification were found in 11 patients. Aberrations in bypass tracks including AKT2, ALK, DDR2, ERBB2/3, HRAS, JAK1/2, KRAS, MET, NTRK1, PIK3CA, RIT1, etc. were observed in 45 patients.

      Clearance of EGFR sensitizing mutations at weeks 3 of treatment was associated with favorable ORR (78.7% vs. 33.3%), PFS (9.6 vs. 4.0 months, p<0.001) and OS (21.5 vs. 11.7 months, p<0.001). Clearance of EGFR sensitizing mutations at weeks 6 of treatment was also associated with favorable ORR (80.0% vs. 36.8%) and PFS (8.3 vs. 4.2 months, p<0.001). Presence of T790M at PD was correlated with longer PFS (12.3 vs. 5.5 months, p<0.001) and OS (21.3 vs. 13.2 months, p=0.045). Acquired or enriched TP53 alterations at PD were associated with worse PFS (4.2 vs. 8.3 months, p=0.008).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study revealed diverse resistance mechanisms to osimertinib in Chinese NSCLC patients and urged for new drug discovery or combination strategies to overcome this clinical challenge.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA10.08 - Discussant - OA 10.04, OA 10.05, OA 10.06, OA 10.07 (Now Available) (ID 14565)

      11:45 - 12:00  |  Presenting Author(s): Linda Coate

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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