Casi Clinici di integrazione multiprofessionale: NSCLC stadio III

Casi clinici di integrazione multi-

professionale:

NSCLC stadio III

Biagio Ricciuti

Scuola di Specializzazione in Oncologia Medica

Università degli Studi di Perugia

Outline

• Standard treatment

• Open questions

• Clinical cases

• Future directions

 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

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

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

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.

Auperin et al, Ann Onc 2006

Auperin et al, JCO 2010 NSCLC Collaborative Group, BMJ 1995

Results of treatment in unresectable stage III NSCLC

• Sequential CT/RT: MST 13.7 months and 5-year O S 10.6%

• Concurrent therapy:

• Meta-analysis

: MST 17 months and 5-year OS 15.1%

• PROCLAIM

(standard arm): MOS 25 months, 37% 3-y OS

• RTOG 0617

(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

Attempts to improve outcomes in stage III NSCLC

• Local treatment.

• Systemic therapy:

• New chemotherapy combinations

• Targeted agents

• Immunotherapy

Unanswered questions about chemotherapy in the management of stage III

1. Which Schedule Should Be Selected?

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

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

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

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

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?

MST (mos) 2-y OS (%) 3-y OS (%)

CT/RT 12 29 19

IND 14 31 23

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

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)

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

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 Thalid

omide

1Spiegel D. et al. JCO 2010 ²Sanborn R et al. Cancer 2017. 3Lee SM, et al. JCO 2009; ⁴Hoang T et al. JCO 2012

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

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

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

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

How we treated the patient in 2014? Concurrent CT/RT

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

How we treated the patient in 2017? Concurrent CT/RT

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

• 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

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

Antonia SJ, NEJM, 2017

Antonia SJ, NEJM, 2017

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.

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; ²Kroeze S et al. Cancer Treat Rev 2017;

3Chang J et al. JAMA Oncol 2017; Cassidy R et al. Cancer 2017

Grazie per l’attenzione

Il progresso è la capacità dell’uomo di complicare la semplicità

Thor Heyerdahl