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Wilfried Eberhardt



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    MS 16 - Future Direction of Chemoradiotherapy for Inoperable Non-small Cell Lung Cancer (ID 538)

    • Event: WCLC 2017
    • Type: Mini Symposium
    • Track: Radiotherapy
    • Presentations: 1
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      MS 16.04 - Future Direction of Immuno-Radiotherapy (ID 7719)

      16:45 - 17:05  |  Presenting Author(s): Wilfried Eberhardt

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Introduction: Recently, systemic approaches to inperable non-small-cell lung cancer (NSCLC) in stage IV disease have been significantly improved by the introduction of a new treatment modality: immunotherapy with PD-1 antibodies. Currently, nivolumab is registered for the second-line therapy of NSCLC without prerequisite of PD-L1 expression in tumor tissue. Pembrolizumab has been registered for PD-L1 positive (> or = 1% TPS) patients in second-line and for high expressors (> or = 50% TPS) also in the first-line setting. In some countries already platinum-based combination chemotherapy (CTx) plus pembrolizumab is accepted for first-line therapy of medium expressors (1-49% TPS) and also for high expressors. Other PD-L1 antibodies have already achieved positive phase-III results (atezolizumab) or large phase-III trials have finished accrual and final results are awaited (eg. durvalumab). Based on these paradigms, the rationale for combinations with radiotherapy (RTx) in NSCLC is analyzed and trial design of currently ongoing studies as well as reported signals of first results are summarized. Material and Methods: Clinicaltrials.gov has been searched for ongoing and active clinical trials with immmunotherapy and RTx. We divided NSCLC strategies into a) locally advanced and inoperable NSCLC stage III b) advanced and inoperable stage IV NSCLC (episcopal effect) c) combinations of immunotherapy and stereotactic RTx in early disease NSCLC d) oligometastatic disease. Results: a) introduction of PD-1 antibodies into treatment strategies of inoperable stage III NSCLC will get a significant booster efffect by the recently reported outcome signals of the Pacific Trial looking at durvalumab consolidation therapy versus placebo following concurrent CTx/RTx in stage III NSCLC (press release, AZ, May 2017). PFS was signifcantly longer for the administration of durvalumab as maintenance in this situation. We expect presentation of the final results at an important Lung Cancer conference during this fall. Theroretically, intoduction by DNA double-strand breaks in patients following concurrent CTx/RTx or RTx alone could lead to an increase in tumor mutational load and could potentially enhance the efficacy of any PD-1- or PD-L1-antibody therapy. A consolidation therapy of PD-1-antibody treatment following concurrent chemoradiotherapy aiming at cure was found to be a rational strategy to improve long-term survival results in inoperable stage III NSCLC. Other trials ongoing are looking at combinations of RTx with concurrent PD-1 immunotherapy or concurrent CTx/RTx combined with concurrent adminstration of PD-1 antibody therapy.Trials outlines will be summarized and presented. Only one phase-II study including pembrolizumab has maintenenance has already been presented with ist results at ASCO 2017. Treatement was manageable and toxicity acceptable. First signals shown efficacy of this strategy but final survival data are pending. Other clincial trials are currently also looking at combinations of CTx and PD-1-immunotherapy and concurrent RTx. Also other immunotherapy drugs such as CTLA4-antibodies or combinations of both PD-1(eg. nivolumab, pembrolizumab, atezolizumab, durvalumab) and CTLA4-antibodies (ipilimumab, tremelimumab) are also being investigated in stage III NSCLC. b) few trials are also looking to enhance systemic effects of immunotherapy (PD-1/PD-L1 and CTLA-4) and concurrent RTx of tumor lesions. The so called "episcopal effect" is being investigated within several clinical studies. Theoretically, the release of tumor associated antigens (TAA) by RTx given to specific tumor lesions leading to tumor lysis including the release of antigens into the circulation could potentially enhance the systemic immunological effects of checkpoint-inhibitor therapies. Well-selected case reports have given hints to support such thesis but only randomized trials will finally verify if this approach is really valid and worthwhile. c) the stereotactic and, therefore, locally ablative RTx techniques also aiming at early inoperable NSCLC patients could also potentially benefit from combinations with new immunotherapy. Several trials are underway for combinations with nivolumab, pembrolizumab, atezolizumab and durvalumab. Finally, for all mentioned treatment strategies concurrent versus sequential administration of immunotherapy and RTx is a complete open issue. Also, permutations including combinations together with platinum-based CTx and immunotherapy together with RTx have recently become very attractive. d) Last but not least, the patient group of oligometastatic patients (M1a, M1b, M1c with less than four lesions in one organ, eg. brain) seems to be a very interesting group of patients to increase both local as well as systemic control of the treatment. Conclusions: Consolidation durvalumab may potentially become the first strategy to become a new paradigm of treatment for stage III NSCLC. We will have to wait for the final results of that trial to draw more valid conclusions for future treatment strategies. However, based on the inclusion of new immunotherapy with checkpoint inhibitors already into the standard treatment algorithms of stage IV disease in NSCLC it can be predicted that also in other disease settings these innovative approches may finally extend our potential treatment options - at least for well selected patient subsets. Referrences: Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 Jun 28;366(26):2455-65. doi: 10.1056/NEJMoa1200694. Epub 2012 Jun 2. Rizvi NA, Mazières J, Planchard D,et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015 Mar;16(3):257-65. doi: 10.1016/S1470-2045(15)70054-9. Epub 2015 Feb 20. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. doi: 10.1056/NEJMoa1504627. Epub 2015 May 31. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. doi: 10.1056/NEJMoa1507643. Epub 2015 Sep 27. Garon EB, Rizvi NA, Hui R, et al. 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. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-50. doi: 10.1016/S0140-6736(15)01281-7. Epub 2015 Dec 19. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. doi: 10.1016/S0140-6736(16)32517-X. Epub 2016 Dec 13. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. Hellmann MD, Rizvi NA, Goldman JW,et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 2017 Jan;18(1):31-41. doi: 10.1016/S1470-2045(16)30624-6. Epub 2016 Dec 5. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. doi: 10.1016/S1470-2045(16)30498-3. Epub 2016 Oct 10. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015 Apr 3;348(6230):124-8. doi: 10.1126/science.aaa1348. Epub 2015 Mar 12. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2017/imfinzi-significantly-reduces-the-risk-of-disease-worsening-or-death-in-the-phase-iii-pacific-trial-for-stage-iii-unresectable-lung-cancer-12052017.html

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    P3.01 - Advanced NSCLC (ID 621)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.01-088 - Molecular Testing and First-Line Treatment of Patients with NSCLC. First Results from the German CRISP Study (AIO-TRK-0315) (ID 9960)

      09:30 - 09:30  |  Author(s): Wilfried Eberhardt

      • Abstract
      • Slides

      Background:
      Treatment of non-small cell lung cancer (NSCLC) is quickly evolving. New biomarkers and targeted agents have been approved at a rapid pace. It is of high interest to patients, physicians and reimbursement institutions to investigate molecular testing and subsequent treatment decisions in routine practice.

      Method:
      The prospective, national clinical research platform CRISP recruits patients in up to 150 cancer centres in all therapeutic sectors in Germany. Patients will be followed until death or for a maximum of 3 years. Raw data from 717 patients recruited by 78 centers by April 03[rd] was analysed regarding molecular testing and 1[st]-line treatment.

      Result:
      Data on histology was available for 635 patients, 71% non-squamous carcinoma (nsqc), 18% squamous carcinoma (sqc). Median age was 67 years and 61% of patients were male. 11% of patients were never smokers. In patients with nsqc (n=507) molecular test rates for EGFR, ALK, ROS-1 and PD-L1 were 69%, 65%, 51% and 26%, respectively. The overall PD-L1 test rate (nsqc & sqc) was 21% in 2016 and has been 27% so far in 2017. Of patients for whom test results were available at time of analysis 58% (n=87) were PD-L1 positive (nsqc 60%, n=76 and sqc 46%, n=11). An EGFR alteration was detected in 16% (n=57), an ALK alteration in 8% (n=25), and a ROS-1 alteration in 4% (n=9) of nsqc patients. Overall, 53% of patients received a carboplatin-based, 22% a cisplatin-based, and 7% a platin-free chemotherapy, while 14% received targeted and 4% other (experimental) therapies. Patients with EGFR alterations (n=57) were most frequently treated with 1[st]-line afatinib (33%), erlotinib (12%), or gefitinib (11%). Patients with ALK alterations (n=25) were most frequently treated with 1[st]-line crizotinib (48%). Patients with PD-L1 positive tumours were most frequently treated with platinum based doublet therapies (carboplatin combined with gemcitabine/taxane/pemetrexed or cisplatin combined with pemetrexed) or with pembrolizumab. The use of 1[st]-line pembrolizumab increased from 7% to 16% from 2016 to 2017. An update with data collected until October 2017 (>1,100 patients expected) will be presented.

      Conclusion:
      For the first time, CRISP presents real life data from all therapeutic sectors in Germany. Patients are frequently tested for molecular alterations and more than half of the patients with molecular alterations can start 1[st]-line treatment with a targeted therapy. Supported by AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer and Roche.

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