casi clinici di integrazione multi- professionale: nsclc...
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Casi clinici di
integrazione multi-
professionale:
NSCLC stadio III
Biagio Ricciuti
Scuola di Specializzazione in
Oncologia Medica
Università degli Studi di
Perugia
Stage III NSCLC Biagio Ricciuti
Stage III NSCLC Biagio Ricciuti
Outline
• Standard treatment
• Open questions
• Clinical cases
• Future directions
Stage III NSCLC Biagio Ricciuti
Heterogeneity in disease
8th 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
HETEROGENEITY OF UNRESECTABLE STAGE III NSCLC
≠
Approaches to the Management of Locoregional NSCLC
Imaging CT-scan*
Invasive LN Result
Therapeutic Approach
No enlarged LNs and
peripheral tumor
Not required if
negative LNs on PET
N0-N1
Adjuvant chemotherapy
(radiotherapy)
Extensive mediastinal
N2 infiltration Not required
No enlarged N2
nodes but central
tumor or hilar LNs
Enlarged discrete N2
LNs
N2
N3
Dedicated
multidisciplinary
assessment
Surgical
multimodality
treatment
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.
Category Of N2
Surgery
Unforeseen N2
Potentially
resectable N2
Unresectable
N2
Stage III NSCLC Biagio Ricciuti
Stage III NSCLC Biagio Ricciuti
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
Evolution of Treatment for Unresectable Stage III NSCLC
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, 0.81-0.98; 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, 0.74-0.95; 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.
Stage III NSCLC Biagio Ricciuti
Auperin et al, Ann Onc 2006
Auperin et al, JCO 2010
NSCLC Collaborative Group, BMJ 1995
Stage III NSCLC Biagio Ricciuti
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-analysis1: MST 17 months and 5-year OS 15.1%
• PROCLAIM2 (standard arm): MOS 25 months, 37% 3-y OS
• RTOG 06173 (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. 2010.2Senan S, et al. J Clin Oncol. 2016. 3Bradley J et al, Lancet Oncol 2015
Stage III NSCLC Biagio Ricciuti
Attempts to improve outcomes
in stage III NSCLC
• Local treatment.
• Systemic therapy:
• New chemotherapy combinations
• Targeted agents
• Immunotherapy
Stage III NSCLC Biagio Ricciuti
Unanswered questions about chemotherapy in the management of stage III
1. Which Schedule Should Be Selected?
Stage III NSCLC Biagio Ricciuti
What is the best regimen to be selected?
• ESMO guidelines1:
• 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 guidelines2:
• 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; 2Bezjak A et al. J Clin Oncol 2015
Stage III NSCLC Biagio Ricciuti
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/RT1
• 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
Stage III NSCLC Biagio Ricciuti
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
2 cycles of etoposide + cisplatin + radiation therapy sequenced to 2 cycles of platinum doublet consolidation
Primary Endpoint : Overall Survival
Superiority design 80% Powered to detect HR =0.74
Senan S et al. J Clin Oncol 2016
R
Stage III NSCLC Biagio Ricciuti
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
Stage III NSCLC Biagio Ricciuti
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?
Stage III NSCLC Biagio Ricciuti
MST (mos)
2-y OS (%)
3-y OS (%)
CT/RT
12
29
19
IND 14 31 23
Vokes E. JCO 2007. Hanna H. JCO 2008
All Patients: Median: 21.1 months Observation: Median: 24.1 months
Docetaxel: Median: 21.5 months P-value: 0.940
No benefit for induction or consolidation based on RCTS
Stage III NSCLC Biagio Ricciuti
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 40-50 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)
Stage III NSCLC Biagio Ricciuti
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 RT2
1Bentzen SM, Nat Clin Pract Oncol 2007 2Koh PK. Cancer Treat Rev 2016
Stage III NSCLC Biagio Ricciuti
Disappointing results with antiangiogenic agents in combination with CT/RT
• Bevacizumab + Carboplatin/pemetrexed/ RT1:
• 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 recommended2
• 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 2010 2Sanborn R et al. Cancer 2017. 3Lee SM, et al. JCO 2009; 4Hoang T et al. JCO 2012
Stage III NSCLC Biagio Ricciuti
EGFR mABs + CT/RT
• Cetuximab:
• Promising phase II data (RTOG 03241).
• Negative results in several trials (RTOG 0839, CALGB 304073) and particularly in
RTOG 0617.
• The use of cetuximab has no meaningful effect on overall survival.
• Panitumumab
• Randomized phase II in combination with wCP/RT in the preoperative setting5.
• No benefit in outcomes and unexpected high mortality rate.
1Blumenschein GR et al. J Clin Oncol 2011; 3Govindan R et al. J Clin Oncol 2011. 4Bradley J et al. Lancet Oncol 2015.5 Edelman M et al. J Thorac Oncol 2017
Stage III NSCLC Biagio Ricciuti
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/RT3
• Erlotinb/RT after carboplatin/nab-paclitaxel4.
• As maintenance
• Gefitinib after PE/RT (S00235), Erlotinib6
1Niho S. et al. Ann Oncol 2012; 2Ready N et al. J Thorac Oncol 2010 3Komaki R et al. J Clin Oncol 2011; 4Lilenbaum R. et al. J Thorac Oncol 2015
5Kelly K et al. J Clin Oncol 2008; 6Casal J et al. Cancer Chemother Pharmacol 2014
Stage III NSCLC Biagio Ricciuti
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 31101
• Randomized phase II
• Primary endpoint P F S
Stage III NSCLC Biagio Ricciuti
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
Stage III NSCLC Biagio Ricciuti
May 2014 August 2014 December 2014
How we treated the patient in 2014? Concurrent CT/RT
Stage III NSCLC Biagio Ricciuti
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
Stage III NSCLC Biagio Ricciuti
April 2017 August 2017 January 2018
How we treated the patient in 2017? Concurrent CT/RT
Stage III NSCLC Biagio Ricciuti
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
Stage III NSCLC Biagio Ricciuti
• 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
IMMUNOTHERAPY + RT
Stage III NSCLC Biagio Ricciuti
PACIFIC: STUDY DESIGN PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER,
INTERNATIONAL STUDY
*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: NCT02125461 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
• 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)
Durvalumab
10 mg/kg q2w for
up to 12 months
N=476
Placebo
10 mg/kg q2w for
up to 12 months
N=237
2:1 randomization,
stratified by age, sex,
and smoking history
N=713
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
Co-primary endpoints
• Progression-free survival (PFS) by
BICR using RECIST v1.1*
• Overall survival (OS)
R
1–42 days
post-cCRT
Stage III NSCLC Biagio Ricciuti
Antonia SJ, NEJM, 2017
Stage III NSCLC Biagio Ricciuti
Antonia SJ, NEJM, 2017
Stage III NSCLC Biagio Ricciuti
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.
Stage III NSCLC Biagio Ricciuti
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 needed2,3
• 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; 2Kroeze S et al. Cancer Treat Rev 2017; 3Chang J et al. JAMA Oncol 2017; Cassidy R et al. Cancer 2017
Stage III NSCLC Biagio Ricciuti
Grazie per l’attenzione
Il progresso è la capacità dell’uomo di complicare la semplicità
Thor Heyerdahl