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N. Hanna

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    PC02 - By 2030 Chemotherapy will Remain Standard of Care for the Majority of Patients with NSCLC Stages I-IV (ID 324)

    • Event: WCLC 2016
    • Type: Pro Con
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      PC02.02 - Pro Chemotherapy (ID 6596)

      14:30 - 15:45  |  Author(s): N. Hanna

      • Abstract
      • Presentation
      • Slides

      Despite the reduction in cigarette consumption in many parts of the world, the incidence and mortality rate of lung cancer will remain high in the year 2030[1]. Over the last 50 years major advances in the treatment of lung cancer have included early detection by screening CT, improved cure rates with neo-adjuvant and adjuvant chemotherapy, the successful integration of chemotherapy with radiation for locally advanced disease, and prolonged survival times with chemotherapy in the metastatic setting. More recently, the discovery of targetable mutations and development of a myriad of small molecule tyrosine kinase inhibitors have transformed the natural history of lung cancer in select subsets. Furthermore, immunotherapy is now a reality in the treatment of patients with stage IV non-small cell lung cancer (NSCLC). Today, the integration of targeted agents and immunotherapy are being investigated in earlier stages of disease. With these recent advances, what does the future of chemotherapy hold in the treatment of stage I-IV NSCLC? Is there a future at all? Can we eliminate the need for chemotherapy altogether for most patients at any point in their disease history? The dream of replacing chemotherapy with more active, less toxic, and more convenient therapy for patients with stage I-IV NSCLC is a laudatory goal. Is it realistic by the year 2030? Certainly not. Chemotherapy is currently the only systemic therapy that has ever been known to cure patients in the neo-adjuvant or adjuvant setting for stage I-III NSCLC[2]. While many targeted agents can prolong life in the metastatic setting, to date all of those tested in the adjuvant setting have failed to improve upon standard therapy[3-5]. The graveyard of negative trials in the adjuvant setting includes those evaluating angiogenesis inhibition, epidermal growth factor tyrosine kinase inhibition, and vaccine therapy. The same can be said for locally advanced, unresectable NSCLC. While the integration of chemotherapy with radiation improves survival rates compared with radiation alone[6], thus far no other agents have successfully done so, including tyrosine kinase inhibitors, angiogenesis inhibitors, or monoclonal antibodies[7-8]. In the metastatic setting, chemotherapy improves survival whether given as induction therapy or as maintenance therapy. Chemotherapy is also more active than targeted therapy in the vast majority of patients who do not harbor targetable mutations. Even with the stunning success of immunotherapy for some patients with advanced NSCLC, it appears this will not be curative in this setting and nearly all patients will still be getting chemotherapy at some point of their disease history. In other words, chemotherapy works for patients with stage I-IV NSCLC. Just as we will do with targeted therapy and immunotherapy, we will not abandon what works, but rather we will improve upon it. Chemotherapy works in a broad group of patients with lung cancer. It targets DNA, topoisomerase, and the mitotic spindle, which are the key targets in all cells. The majority of patients’ tumors do not have targetable mutations and most patients do not respond to immunotherapy. While gains are expected over the next 15 years in targeted therapy and immunotherapy, it is likely that we will discover the plateau in the benefit to these strategies and eventually nearly all patients will develop resistance. While predicting the future is usually only a fool’s errand, the past is prologue. So, what is the future of chemotherapy in NSCLC? Better drug delivery systems; developing combination therapy with DNA repair agents, cell cycle checkpoint modulators, and immunotherapy; and improved biomarkers for efficacy and toxicity are each on the horizon. Improved targeting of the cancer cell, increased cancer cell drug concentrations, and reduction of normal cell toxicity can be accomplished through nano-carriers[9]. Nano-carriers can deliver chemotherapy directly to cancer cells by protecting these agents from being degraded in the circulation and being excessively protein bound, limiting active drug exposure. Nano-carriers include liposomes, carbon nanotubes, dendrimers, and polymeric compounds (micelles, conjugates, nanoparticles). These carriers are typically 100-150 nm in size but have large surface-to-surface volume ratios, enabling them to encapsulate cytotoxic agents and enhancing drug deliver to tumors. Thus far 8 have been FDA approved, including 2 polymer-protein conjugates, 5 liposomal formulations, and 1 polymeric nanoparticle, in various cancers. Another strategy to enhance drug delivery to tumors is through antibody-drug conjugates (ADC). These agents link an antibody to a protein overexpressed on the surface of a cancer cell to a potent cytotoxic such as a microtubule inhibitor or an alkylating agent. The cytotoxic is released only in the cancer cell after the ADC complex is internalized. Examples include TDM-1 and Brentuximab. Over 30 ADC’s are under clinical investigation, including several against lung cancer including Rova-T and Sacituzumab. Another promising strategy for the future treatment of lung cancer involves combining chemotherapy with drugs that interfere with DNA repair, silence DNA repair genes, or inhibit cell cycle arrest [10]. Examples of this approach include PARP inhibitors, DNA methylation agents, and checkpoint modulators. Combination trials of chemotherapy and immunotherapy are also underway. In this regard, ADC technology may prove a more effective strategy when combining cytotoxic drugs with immunotherapy. By improving chemotherapy drug delivery to cancer cells and reducing off-target toxicities, nanotechnology has the potential to most effectively combine chemotherapy with immunotherapy. Lastly, despite decades of clinical investigation, most patients are empirically treated with chemotherapy, regardless of the molecular characteristics of the tumor and the pharmacogenomics of the patient. Refinements in these areas are expected in the upcoming years. In conclusion, for better or worse, in the year 2030 chemotherapy will remain standard of care for the majority of patients with stage I-IV NSCLC. But, the year 2040 or 2050 may be a different story. References 1. Rahib L, Smith B, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancer in the United States. Cancer Res 2014;74(11):2913-2921. 2. Burdett S, Pignon J, Tierney J, et al. Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Cochrane Database Syst Rev 2015;2(3):doi: 10.1002/14651858.CD011430 3. Wakelee H, Dahlberg S, Keller S, et al. E1505: Adjuvant chemotherapy +/- bevacizumab for early stage NSCLC—Outcomes based on chemotherapy subsets. J Clin Oncol 2006;34(abstract 8507). 4. Kelly K, Altorki N, Eberhardt W, et al. Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non–Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 2015;33:4007-4014. 5. Van Steenkiste J, Zielinski M, Linder A, et al. Adjuvant MAGE-A3 Immunotherapy in Resected Non–Small-Cell Lung Cancer: Phase II Randomized Study Results. J Clin Oncol 2013;31(19):2396-2403. 6. O’Rourke N, Roque i Figuls M, Farre Bernado N, et al. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2010; DOI: 10.1002/14651858.CD002140. 7. Kelly K, Chansky K, Gaspar L, et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 2008;26(15):2450-6. 8. Bradley J, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015;16(2):187-199. 9. Fanciullino R, Ciccolini J, Milano G. Challenges, expectations and limits for nanoparticles-based therapeutics in cancer: a focus on nano-albumin-bound drugs. Crit Rev Onc Hemat 2013;88:504-513. 10. Helleday T, Petermann E, Lundin C, et al. DNA repair pathways as targets for cancer therapy. Nature Rev 2008;8:193-204.

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