Casi clinici di integrazione multiprofessionale: NSCLC stadio III. Biagio Ricciuti. Scuola di Specializzazione in Oncologia Medica

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1 Casi clinici di integrazione multiprofessionale: NSCLC stadio III Scuola di Specializzazione in Oncologia Medica Università degli Studi di Perugia

2 Outline Standard treatment Open questions Clinical cases Future directions

3 HETEROGENEITY OF UNRESECTABLE STAGE III NSCLC Heterogeneity in disease 8 th TNM classification: IIIA vs. IIIB vs. IIIC T3 vs. T4, T size, N2 vs. bulky N2 vs. N3 Wide spectrum in morphological presentation Heterogeneity in individual risk patient profile Pulmonary and cardiovascular comorbidities Inter-institution variability Expertise in radiation oncology Multidisciplinary team High volume vs. low volume centres

4 Approaches to the Management of Locoregional NSCLC Imaging CT-scan* Invasive LN Result Category Of N2 Therapeutic Approach No enlarged LNs and peripheral tumor Not required if negative LNs on PET Surgery Unforeseen N2 Adjuvant chemotherapy (radiotherapy) No enlarged N2 nodes but central tumor or hilar LNs Enlarged discrete N2 LNs N0-N1 N2 N3 Potentially resectable N2 Dedicated multidisciplinary assessment Surgical multimodality treatment Extensive mediastinal N2 infiltration Not required Unresectable N2 Nonsurgical multimodality treatment *Category description according to CT imaging as in ACCP staging document. ACCP = American College of Chest Physicians; CT = computed tomography; LN = lymph node; NSCLC = non-small cell lung cancer; PET = positron emission tomography. Postmus et al.ann Oncol. 2017; 28 (Suppl 4):iv1 iv21.

5 MILESTONES IN THE TREATMENT OF STAGE III NSCLC Dillman, NEJM 1990; Sause, Am J Clin Oncol 1992; Le Chevalier, JNCI 1991; Schaake-Koning, NEJM 1992;; Aupérin, JCO 2010NSCLC Collaborative Group, BMJ 1995

6 Evolution of Treatment for Unresectable RT vs Sequential Chemotherapy/RT RT vs Concurrent Chemotherapy/RT Sequential vs Concurrent Chemotherapy/RT A significant overall benefit from chemotherapy was observed. The HR of 0.90 (p = 0.006), or 10% reduction in the risk of death, corresponded to absolute benefits of 3% at 2 years and 2% at 5 years The HR of death of radio-chemotherapy compared to radiotherapy alone was 0.89 (95% CI, ; p=0.02). This corresponds to an absolute benefit of chemotherapy of 4% at 2 years and 2.2% at 5 years A significant benefit of concomitant RT-CT as compared with sequential RT-CT was observed (HR, 0.84; 95% CI, ; p=0.004), with an absolute survival benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% (10.6% to 15.1%) at 5 years. NSCLC Collaborative Group, BMJ 1995 Auperin et al, Ann Onc 2006 Auperin et al, JCO 2010

7 Results of treatment in unresectable stage III NSCLC Sequential CT/RT: MST 13.7 months and 5-year O S 10.6% 1 Concurrent therapy: Meta-analysis 1 : MST 17 months and 5-year OS 15.1% PROCLAIM 2 (standard arm): MOS 25 months, 37% 3-y OS RTOG (standard arm): MOS 28.7 months and 58% 2-y OS Although the goal is to cure, less than 25% of patients experience 5-y survival and are presumably cured. 1Auperin A, et al. J Clin Oncol Senan S, et al. J Clin Oncol Bradley J et al, Lancet Oncol 2015

8 Attempts to improve outcomes in stage III NSCLC Local treatment. Systemic therapy: New chemotherapy combinations Targeted agents Immunotherapy

9 Unanswered questions about chemotherapy in the management of stage III 1. Which Schedule Should Be Selected?

10 What is the best regimen to be selected? ESMO guidelines 1 : In the absence of contraindications, the optimal CT to be combined with RT should be based on cisplatin. [I, A]. Most comparative studies were using cisplatin/etoposide or cisplatin/vinca alkaloid (typically: cisplatin/vinorelbine), or cisplatin/pemetrexed if non- squamous histology. ASCO guidelines 2 : The ideal concurrent chemotherapy regimen has not been determined. The two most common regimens are cisplatin/etoposide and carboplatin/paclitaxel. 1Postmus P et al. Ann Oncol 2017; 2 Bezjak A et al. J Clin Oncol 2015

11 What is the best CT regimen to use concomitantly with TRT? The most used regimen in R C T s is E P but weekly C P emerged as an alternative choice because of the toxicity. However, there is considerable concern that C P, although better tolerated than E P, may be inferior in terms of disease control. Phase III EP/RT vs weekly PC/RT 1 N: 200 patients MST: E P 23.3 m vs 20.7 m P C (HR 0.76; p: 0.095) 5-y O S: E P 28% vs PC 19.7% More G2 > pneumonitis with CP (33%) /esophagitis with E P (20%) Conclusions: EP might be superior to weekly P C in terms of O S Liang et al, Ann Oncol 2017

12 Full dose second generation (EP) versus third generation (PP) in nsq NSCLC: PROCLAIM study Rand 1:1 Stratify by: - PS 0 vs 1 - Gender - IIIA vs IIIB -PET scan use N: 600 pts R 3 cycles* of pemetrexed + cisplatin + radiation therapy sequenced to 4 cycles of pemetrexed Primary Endpoint : Overall Survival Superiority design 80% Powered to detect HR = cycles of etoposide + cisplatin + radiation therapy sequenced to 2 cycles of platinum doublet consolidation Senan S et al. J Clin Oncol 2016

13 PROCLAIM study: Results Enrolment was stopped early because of futility. 598 patients were randomized. Pem/Cisplatin was not superior to P E in terms of O S (HR 0.98; MOS 26.8 v 25.0 months; P =.831). No new safety issues were identified. Pem/cisplatin had a significantly lower incidence of any drug-related grade 3 to 4 adverse events (64.0% v 76.8%; P =.001). Senan S, J Clin Oncol 2016

14 Unanswered questions about chemotherapy in the management of stage III 1. Which schedule should be selected? 2. Is there any role for induction or consolidation?

15 No benefit for induction or consolidation based on RCTS MST (mos) 2-y OS (%) 3-y OS (%) CT/RT IND All Patients: Median: 21.1 months Observation: Median: 24.1 months Docetaxel: Median: 21.5 months P-value: Vokes E. JCO Hanna H. JCO 2008

16 WHICH CHEMOTHERAPY REGIMEN? Are the new regimen better than the old generation regimen? Most frequently used regimen US cisplatin-etoposide (cisplatin 50 mg/m² d1, d8 + etoposide 50 mg/m² d1-d5) carboplatin-paclitaxel (carboplatin AUC=2/wk+ paclitaxel mg/m²/wk) Europe cisplatin-vinorelbine (cisplatin 80 mg/m² d1 + vinorelbine15 mg/m² d1, d8) Japan cisplatin-docetaxel (cisplatin 40 mg/m² + docetaxel 40 mg/m² d1, d8, d29, d36)

17 Targeted agents in the setting of unresectable stage III A therapeutic plateau has been reached using CT/RT. There is a clear rationale to combine targeted agents to RT. 1 Normalization of tumor blood vessels could improve hypoxia, improving radiosensitivity and drugs delivery. The overexpression of EG F R is correlated with increased radioresistance, thus targeting E G F R could have a radiosensitizing effect. So far, none of the targeted agents tested have shown proven benefit when combined with RT 2 1 Bentzen SM, Nat Clin Pract Oncol Koh PK. Cancer Treat Rev 2016

18 Disappointing results with antiangiogenic agents in combination with CT/RT Bevacizumab + Carboplatin/pemetrexed/ RT 1 : Tracheo-oesophageal fistulation prompting early trial closure, FDA warning and change of labelling. Vandetanib + PE/TRT in SCLC: The toxicity was increased and the combination was not recommended 2 Thalidomide + CT/RT 3,4 2 Phase III Similar MST, P F S and R. R Higher incidence of G >3 in the Thalidomide arm 1Spiegel D. et al. JCO Sanborn R et al. Cancer Lee SM, et al. JCO 2009; 4 Hoang T et al. JCO 2012

19 EGFR mabs + CT/RT Cetuximab: Promising phase II data (RTOG ). Negative results in several trials (RTOG 0839, CALGB ) and particularly in RTOG The use of cetuximab has no meaningful effect on overall survival. Panitumumab Randomized phase II in combination with wcp/rt in the preoperative setting 5. No benefit in outcomes and unexpected high mortality rate. 1Blumenschein GR et al. J Clin Oncol 2011; 3 Govindan R et al. J Clin Oncol Bradley J et al. Lancet Oncol Edelman M et al. J Thorac Oncol 2017

20 EGFR TKI s are not beneficial in stage III unselected population Different approaches but disappointing results. As induction treatment Gefitinib /cisplatin/vinorelbine (JCOG0402) 1 As concurrent therapy Gefitinib/RT or Gefitinb/wkcarboplatin/paclitaxel/RT(CALEB study) 2 ; Erlotinib/wkcarboplatin/paclitaxel/RT 3 Erlotinb/RT after carboplatin/nab-paclitaxel 4. As maintenance Gefitinib after PE/RT (S ), Erlotinib 6 1 Niho S. et al. Ann Oncol 2012; 2 Ready N et al. J Thorac Oncol Komaki R et al. J Clin Oncol 2011; 4 Lilenbaum R. et al. J Thorac Oncol Kelly K et al. J Clin Oncol 2008; 6 Casal J et al. Cancer Chemother Pharmacol 2014

21 Targeted agents in molecular selected population The integration of targeting agents will be challenging. Small number of patients Unclear sequence to be tested. Difficulties to define robust endpoint in R C T due to crossover. R T O G 1306/ALLIANCE Randomized phase II Primary endpoint P F S

22 Case #1 65 years old Female Current smoker (60 p/y) EGFR/ALK/ROS1 negative, KRAS mutant Gly12Cys COPD, Hypertension Salmeterol/fluticasone, ramipril Unresectable stage III lung adenocarcinoma (ct3n2m0 - IIIB) May 2014

23 How we treated the patient in 2014? Concurrent CT/RT May 2014 August 2014 December 2014

24 Case #2 45 years old Female Never smoker EGFR/ALK/KRAS/ROS1/RET/ MET/HER2 negative No comorbidities No drugs Unresectable stage III squamous lung cancer (ct4n2m0 - IIIB) April 2017

25 How we treated the patient in 2017? Concurrent CT/RT April 2017 August 2017 January 2018

26 How we would treat patients today? Concurrent chemo-radiotherapy Cisplatin plus VP16/Taxanes/Vinca Alkaloids + RT 60 Gy in 30 fractions Durvalumab 10 mg/kg every two weeks for 12 months

27 IMMUNOTHERAPY + RT There is a strong rationale to combine RT and I C I RT can cause immunogenic cell death, modulate antigen presentation and alter the microenvironment within the irradiated field. Since ICPI s have shown clinical benefit in advanced NSCLC, the next step is to explore these agents in the stage III setting. Two modalities: Antigen specific cancer vaccine ICPI

28 PACIFIC: STUDY DESIGN PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER, INTERNATIONAL STUDY Patients with stage III, locally advanced, unresectable NSCLC who have not progressed following definitive platinum-based ccrt ( 2 cycles) 18 years or older WHO PS score 0 or 1 Estimated life expectancy of 12 weeks All-comers population (i.e. any PD-L1 status) 1 42 days post-ccrt R Durvalumab 10 mg/kg q2w for up to 12 months N=476 2:1 randomization, stratified by age, sex, and smoking history N=713 Placebo 10 mg/kg q2w for up to 12 months N=237 Co-primary endpoints Progression-free survival (PFS) by BICR using RECIST v1.1* Overall survival (OS) Secondary endpoints Proportion of patients alive and progression-free at 12 and 18 months (per BICR) ORR (per BICR) DoR (per BICR) OS at 24 months Safety and tolerability Health-related quality of life Pharmacokinetics Immunogenicity *Defined as the time from randomization (which occurred up to 6 weeks post-ccrt) to the first documented event of tumor progression or death in the absence of progression. ClinicalTrials.gov number: NCT BICR, blinded independent central review; ccrt, concurrent chemoradiation therapy; DoR, duration of response; HR, hazard ratio; ITT, intention-to-treat; NSCLC, non-small cell lung cancer; ORR, objective response rate; PS, performance status; q2w, every 2 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; WHO, World Health Organization

29 Antonia SJ, NEJM, 2017

30 Antonia SJ, NEJM, 2017

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32 Ongoing trials addressing the role of ICPI in stage III NSCLC The synergistic combination of RT and IT has a promising potential but several issues (synergy, timing, doses) need to be considered, in particular the potential risk of increasing toxicities.

33 FUTURE DIRECTIONS Combining RT with PARP inhibitors No benefit in outcomes compared to placebo in a RCT in patients with brain metastases treated with whole-brain RT. 1 SBRT or Proton therapy and systemic treatments Even though these combinations are increasingly performed, available safety information is very limited and further optimization is still needed 2,3 Analysis of the influence of genetics alterations to guide treatment. RAS mutations associated with worse local control and MET amplification with worse regional and distant disease control in early stages treated with SBRT 4 1Chabot P et al. J Neurooncology 2017; 2 Kroeze S et al. Cancer Treat Rev 2017; 3Chang J et al. JAMA Oncol 2017; Cassidy R et al. Cancer 2017

34 Grazie per l attenzione Il progresso è la capacità dell uomo di complicare la semplicità Thor Heyerdahl