ΘΕΡΑΠΕΙΑ ΜΙΚΡΟΚΥΤΤΑΡΙΚΟΥ ΚΑΡΚΙΝΟΥ ΠΝΕΥΜΟΝΑ. Σοφία Παπακάτσικα ειδικευόμενη Ογκολογίας

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1 ΘΕΡΑΠΕΙΑ ΜΙΚΡΟΚΥΤΤΑΡΙΚΟΥ ΚΑΡΚΙΝΟΥ ΠΝΕΥΜΟΝΑ Σοφία Παπακάτσικα ειδικευόμενη Ογκολογίας

2 ΜΙΚΡΟΚΥΤΤΑΡΙΚΟ CA ΠΝΕΥΜΟΝΑ (SCLC) 15% όλων των περιπτώσεων Ca πνεύμονα νευροενδοκρινική διαφοροποίηση συχνά 70% extensive-stage κατά τη διάγνωση (απουσία συμπτωμάτων, μεθόδων screening) καλή απάντηση στην αρχική θεραπεία ταχεία υποτροπή και αντοχή στις επόμενες γραμμές median OS after relapse: 7-12 mo

3 SCLC TREATMENT ένδεια μεθόδων έγκαιρης διάγνωσης περιορισμένη διάθεση βιοπτικού υλικού για περαιτέρω έρευνα ταχεία εξέλιξη της νόσου

4 STAGING 2 συστήματα VALG (veterans administration lung study group) AJCC TNM

5 STAGING-VALG

6 STAGING-TNM

7 STAGING-TNM

8 TNM-STAGE GROUPING

9 STAGING-TNM limited-stage: any T, any N that is a confined to a single radiation field extensive-stage: any T, any N than extend beyond a single radiation field, M1a/b/c TNM mainly useful for patients eligible for surgical resection

12 SCLC-SURGERY ESMO : ct1-2 cn0-1 M0 resectable (no biopsy before surgery) συμπληρωματική (adjuvant) 4 cycles Χ/Θ +/- RT

13 LIMITED STAGE SCLC limited-stage in excess of St I do not benefit from surgery standard-of-care: concurrent CRT with curative intent (good PS) up to 25% 5-y survival

14 SCLC-ΑΡΧΕΣ ΘΕΡΑΠΕΊΑΣ Σημαντική η άμεση έναρξη θεραπείας Μονήρης μεταστατική εστία υπό διερεύνηση: έναρξη θεραπείας προ ιστολογικής ταυτοποίησης και επανεκτίμηση μετά 2 κύκλους θεραπείας multimodality treatment for limited-stage

15 CHEMO FOR LIMITED STAGE Χ/Θ συνδυασμού με βάση την πλατίνα Cisplatin-etoposide η κλασική επιλογή βάσει μελετών Cisplatin 60 mg/m2 d1, etoposide 120 mg/m2 d1-d3 (q21d) 4-6 κύκλοι θεραπείας δεν έχουν ένδειξη dose-dense σχήματα

16 EXTENSIVE STAGE < 5% over 2-y survival median PFS: 2-6 mo, median OS: 9-10 mo chemotherapy alone (good PS/poor PS due to SCLC) no benefit from consolidation treatment

17 CHEMO FOR EXTENSIVE STAGE συνδυασμένη θεραπεία με βάση την πλατίνα (carbo-etoposide ή cisplatin-etoposide) όχι μονοθεραπεία ταχεία υποστροφή νόσου (2ο κύκλο) και βελτίωση ποιότητας ζωής

18 CISPLATIN OR CARBOPLATIN?

20 m OS: 9,6 vs 9,4 mo m PFS: 5,5 vs 5,3 mo

22 CISPLATIN OR CARBOPLATIN?

23 CISPLATIN OR CARBOPLATIN?

24 IRINOTECAN 1ST LINE irinotecan in 1st line a challenging option median survival: 12,8 vs 9,4 mo (p=0,002)

25 IRINOTECAN 1ST LINE

26 IRINOTECAN VS ETOPOSIDE

27 IRINOTECAN VS ETOPOSIDE IP vs EP: no significant differences in OS, time to progression

28 IRINOTECAN VS ETOPOSIDE

oncogenic driver, mostly passenger mutations common TP53, RB

29 TARGETED THERAPIES high mutational burden (smoking) tumor heterogeneity at the genetic level no clear targetable oncogenic driver, mostly passenger mutations common TP53, RB mutations cross-institutional effort to achieve better molecular profiling

31 SECOND-LINE TREATMENT early relapse (<6 weeks) resistant ( platinum-refractory ) disease (<3 months) sensitive disease (>3 months) duration of response to front-line therapy affects response to further treatment BSC is preferred

32 SECOND-LINE TREATMENT early relapse (6 weeks): BSC or clinical trial resistant disease (relapse <3 mo), PS 0-2: topotecan/irinotecan/paclitaxel/docetaxel/im munotherapy/ CAV no difference in OS oral topotecan is the approved treatment after relapse rechallenge with PE benefits sensitive disease only

33 IMMUNOTHERAPY FOR SCLC

34 IMMUNOTHERAPY FOR SCLC low PD-L1 expression in most SCLCs tumor mutational burden (TMB) a possible biomarker high TMB predicts PFS and response-rate after immunotherapy TMB correlates with neo-antigen load in the tumor needs broad panel of sequencing

36 rrelation between TMB and objective response rate with anti-pd1 or anti-pd-l1 therapy in 27 tumor type

42 1-y OS 33% nivo 43% nivo+ipi durable responses irrespective of platinum-sensitivity, line of treatment or PD-L1 expression status

43 OS (%) Checkmate 032: OS in Non-Randomized Cohort Events/Num ber at Risk Median OS, months (95% CI) Nivolumab 82/ (3.0, 6.8) Nivolumab + Ipilimumab 1-yr OS=40% 1-yr OS=27% 47/ (3.6, 14.2) 2-yr OS=26% 2-yr OS=14% Minimum Follow-up,* months Number of Patients at Nivolum Risk Nivolumab + Ipilimuma b Time (months) *Between first dose and database lock; follow-up shorter for patients who died prior to database lock. Hellmann M et al. Oral presentation at ASCO Abstract Abbreviations can be found in the speaker notes. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES. 69

46 8/2018 accelerated FDA approval of nivolumab for SCLC which progressed on at least 2 previous lines of treatment

47 THE ROLE OF RADIOTHERAPY

48 THE ROLE OF RADIOTHERAPY IN LIMITED STAGE all inoperable with good PS start early (2nd cycle) concurrently with chemo 60 Gy in total (once-daily schedule) in 5 w 45 Gy (BID schedule, 1,5 Gy daily dose)-shorter duration-3w, decreased radiation dose sequential RT for poor PS (3-4) due to SCLC

50 primary endpoint: m OS 30 mo (bid) vs 25 mo (od)

51 THE ROLE OF RADIOTHERAPY IN EXTENSIVE STAGE extensive-stage pts that respond well to initial treatment (CR/PR) sequential consolidative thoracic RT improves 2-y survival rate and 6-month PFS mainly benefits low-bulk extrathoracic disease

52 THE ROLE OF PCI prophylactic cranial irradiation prevents brain mets 5% OS advantage in limited-stage: resected, CR or PR can be considered for extensive-stage with good response to 1st line treatment 25 Gy in 10 daily sessions is the highest dose no difference in OS in extensive-stage

55 1-y OS rate: 52% vs 38,2% (p=0,007) 1-y PFS: 12,6% vs 5,4% (p=0,02)

57 CHALLENGES IN SCLC TREATMENT to improve duration of responses to front-line therapy to find active treatment after disease relapse better profiling of tumors (better sampling, need for a biomarker to assess response to treatment)

58 REFERENCES 1. NCCN Clinical Practice Guidelines in Oncology, Version Fruh M et al. SCLC: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(Suppl 6):vi99-vi Zhao H, Ren D, Liu H, Chen J. Comparison and discussion of the treatment guidelines for small cell lung cancer. Thoracic Cancer 2018; 9: Byers LA, Rudin CM. Small cell lung cancer: where do we go from here? Cancer 2015; 121(5): Rossi A et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. JCO 2012; 30(14): Noda K et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002; 346: Hanna N et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small cell lung cancer. JCO 2006; 24(13): Tsoukalas N et al. Advanced SCLC: new challenges and new expectations. Ann Trans Med 2018; 6(8): Hagmann R et al. Second-line therapy of small-cell lung cancer: topotecan compared to a combination treatment with adriamycin, cyclophosphamide and vincristine- a single centre experience. J Canc 2015; 6(11): Li Q et al. A new hope: the immunotherapy in small cell lung cancer. Neoplasma 2016; 63(3): Pacheco JM, Cambridge DR. Keynote-028: How do we use immunotherapy in small cell lung cancer? J Clin Oncol 2017;35: Antonia SJ et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (Checkmate-032): a multi centre, open-label, phase 1/2 trial. Lancet Oncol 2016; Published online June 4, Faivre-Finn C et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an openlabel, phase 3, randomised, superiority trial. Lancet Oncol 2017; 18: Horn L et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. DOI: /NEJMoa

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