Terapia personalizata în diagnosticul şi tratamentul neoplasmului bronhopulmonar non-microcelular

Advanced non-small cell lung cancer (NSCLC)

Personalized therapy

Patient-related factors

•  Performance status

•  Co-morbidity, organ functions

•  Age

•  Gender

•  Side effects of drugs

•  Convenience of administration

•  Patient preference

Tumor-related factors

•  Histological subtype

•  Tumor growth

•  Molecular characteristics

Costs, cost effectiveness, value-based judgements

Signature and mutational processes in human cancer
 

(Alexandrov LB et al. Nature, 2013, 500, 415)

Driver mutations
 

(Pao W and Girard N et al. Lancet Oncol, 2011, 12, 175)

Advanced NSCLC

Status September 2015

EGFR mutation-positive tumors

• 30-60% of Asian patients (adenocarcinomas)

• 10-15% of Caucasian patients (adenocarcinomas)

ALK-positive tumors

•  3-5% of patients (adenocarcinomas)

Tumors without targetable driver mutations

• Majority of Caucasian patients with advanced NSCLC

EGFR mutations and response to TKIs
 

 

First-line EGFR TKIs vs. chemotherapy in patients with EGFR mutation

LUX-Lung 3 and LUX-Lung 6: PFS

Independent review
 

 

LUX-Lung 3: Quality of life

(Yang JC-H et al. JCO, 2013, 31, 3342)
 

 

 

 

Afatinib vs chemotherapy for EGFR  mutation-positive lung adenocarcinoma:
LUX-Lung 3 and LUX-Lung 6

(Yang JC-H et al. Lancet Oncol, 2015, 16, 141)
 

Afatinib vs. chemotherapy for EGFR mutation-positive lung adenocarcinoma:
LUX-Lung 3 and LUX-Lung 6

(Yang JC-H et al. Lancet Oncol, 2015, 16, 141)
 

Lung cancer

Molecular diagnosis in Europe

EGFR mutation testing has been established

• European Workshop (Pirker R et al., JTO 2010, 5, 1706)

• INSIGHT project (Ramlau R et al., JTO 2015, 10, 1370)

Routine KRAS testing in some countries, e.g. Hungary

• FR TKIs are approved only for KRAS wild-type patientsEG

• EGFR analysis only in KRAS wild-type patients

ALK analysis

•  IHC screening

•  FISH

French experience (Barlesi F et al., ASCO 2014)

EGFR mutation status
 

First-line therapy
 

Adenocarcinoma with exon 19 deletion
 

EGFR TKI-resistant NSCLC

(Camidge R et al. Nat Rev Clin Oncol, 2014, 11, 473)
 

Treatment at time of TKI resistance

Re-biopsy

Treatment

•  Third generation EGFR TKI

- AZD9291, rociletinib (CO-1686), HM61713

 

• Switch to chemotherapy with potential re-challenge with TKIs after chemotherapy 

•  Continue with TKI

•  Add local therapy to TKI

•  Add chemotherapy to TKI

•  Afatinib plus cetuximab

AZD9291 in EGFR inhibitor-resistant NSCLC

(Jänne PA et al. NEJM, 2015, 372, 1689)

Selective third generation TKI

EGFR mutation-positive patients with acquired resistance to EGFR TKIs (NCT01802632)

Dose escalation and dose expansion cohorts

20-240 mg AZD9291 once daily

Patients (n=253)

Female                                     62%

Asian                                        62%

Adenocarcinoma                      96%

Prior TKIs median                     2 (range 1-5)

Prior chemotherapy                  80%

T790M                                      62%

AZD9291 in EGFR inhibitor-resistant NSCLC

(Jänne PA et al. NEJM, 2015, 372, 1689)
 

AZD9291 in EGFR inhibitor-resistant NSCLC

(Jänne PA et al. NEJM, 2015, 372, 1689)

No dose-limiting toxicity

AE any grade (grade 3-5)

Diarrhea                                       47% (2%)

Rash                                              40% (1%)

Dry skin                                        20% (0)

Puritus                                         19% (0)

Paronychia                                   17% (<1%)

Nausea                                         22% (<1%)

Decreased appetite                     21% (1%)

Fatigue                                         17% (1%)

AE grade 3-5                                  32%

AE gr 3-5 drug-related                  13%

SAE                                                 22%

SAE drug-related                           6%

AZD9291: Clinical studies in EGFR
mutation-positive NSCLC

AURA phase I/II study

AURA 2

•  Phase II trial

AURA 3

• Phase III trial AZD9291 vs. platin-based chemotherapy            in second-line therapy

FLAURA

• Phase III trial AZD9291 vs. gefitinib or erlotinib in                first-line therapy

ADAURA

• Phase III trial AZD9291 vs. placebo as maintenance therapy

ASTRA

•  AZD9291 in early access program

Rociletinib in EGFR-mutated NSCLC

(Sequist LV et al. NEJM, 2015, 372, 1700)

Selective irreversible 3^rd generation drug (activating and T790 mutations)

Phase I study in previously treated patients with EGFR mutation-positive disease (NCT01526928)

CO-1686 free base form up to 900 mg twice daily

CO-1686 hydrogen bromide form 500-1000 mg twice daily

Patients (n=130)

•  Female                77%

•  Asian                                 15%

•  Prior therapies                  median 4

•  Prior TKI median              2

•  T790M                57%

Rociletinib in EGFR-mutated NSCLC

(Sequist LV et al. NEJM, 2015, 372, 1700)
 

Rociletinib in EGFR-mutated NSCLC

(Sequist LV et al. NEJM, 2015, 372, 1700)
 

Rociletinib in EGFR-mutated NSCLC

(Sequist LV et al. NEJM, 2015, 372, 1700)

Dose-limiting toxicities were <33% at all dose levels.

Adverse events (all grades)

Hyperglycemia                36%

Nausea                            31%

Fatigue                            24%

Diarrhea                          20%

Decreased appetite        15%

Rash                               <1%

Hyperglycemia was well managed with oral hypoglycemics and/or dose reduction.

Recommended phase II dose: 750 mg twice daily
 

3^rd generation EGFR tyrosine kinase inhibitors
Summary

Targeting EGFR-activating mutations and T790M mutation while sparing wild-type EGFR  

Response rates around 60%

AZD9291

• Phase III trials: AURA 3, FLAURA, ADAURA

•  ASTRA: Early access program

Rociletinib (CO-1686)

•  TIGER trials

HM61713

Crizotinib in advanced NSCLC

EML4-ALK-positive NSCLC
 

Crizotinib versus chemotherapy in advanced ALK-positive NSCLC: Profile 1007

(Shaw A et al. NEJM, 2013, 368, 2385)

Patients (n=347) pre-treated with chemotherapy

                                                            Crizotinib                          docetaxel or pemetrexed

Response rate                                         65%                                                     20%

PFS median                                        7.7 months                                           3 months
 

First-line crizotinib versus chemotherapyin ALK-positive NSCLC: Profile 1014

(Solomon BJ et al. NEJM, 2014, 371, 2167)
 

Crizotinib-resistant NSCLC

(Camidge R et al. Nat Rev Clin Oncol, 2014, 11, 473)
 

Ceritinib in ALK-rearranged NSCLC

(Shaw A et al. NEJM, 2014, 370, 1189)
 

 

Advanced NSCLC
Palliative 1^st line chemotherapy

Platinum-based doublets with 3^rd generation drug

(vinorelbine, gemcitabine, paclitaxel, docetaxel, pemetrexed, nab-paclitaxel); 4-6 cycles

Symptom relief in approximately 50-60%

1-year survival rate increased by absolute ~10%

Improvement of quality of life (?)     

(NSCLC Collaborative Group. BMJ 1995;311:899-909

NSCLC Meta-Analyses Collaborative Group. J CO 2008;26:4617-25)

Performance status affects outcome.

Elderly patients and patients with poor PS also benefit.

•  Well tolerated protocols

•  Enhanced supportive care

Chemotherapy of advanced NSCLC
Recent developments

Novel cytotoxic drugs

Customized chemotherapy based on biomarkers

Changes in administration and/or schedule

• Oral administration          

• Chronic administration of low doses at regular intervals (metronomic chemotherapy)   

Combination with targeted therapies

•  Angiogenesis inhibitors

 Bevacizumab

 Ramucirumab                   

 Nintedanib

•  Anti-EGFR monoclonal antibodies

 Cetuximab

 Necitumumab

Bevacizumab in advanced non-squamous NSCLC
 

1^st line chemotherapy ± EGFR antibodies: survival
 

1^st line chemo ± necitumumab in squamous NSCLC - overall survival
 

Survival based on biomarkers
 

Chemotherapy ± anti-EGFR antibodies: biomarkers
Summary
 

Maintenance therapy: Phase III trials

Vinorelbine                                                  (Westeel V et al. JCNI, 2005, 97, 499)

 

Gemcitabine

•  CECOG                                                            (Brodowicz T et al. Lung Cancer, 2006, 52, 155)

•  US-Studie                                                         (Belani CP et al. JCO, 2010, 28, 15s (Abstr 7506))

•  IFCT-GFPC                                                      (Perol M et al. JCO, 2012, 30, 35160)

 

Pemetrexed

•  JMEN                                                              (Ciuleanu T et al. Lancet, 2010, 374, 1432)

•  PARAMOUNT                                                 (Paz-Ares L et al. Lancet Oncol, 2012, 13, 247)

•  AVAPERL                                                         (Barlesi F et al. JCO, 2013, 31, 3004 & Ann Oncol, 2014, 25, 1044)

  

Erlotinib

•  SATURN                                                           (Cappuzzo F et al. Lancet Oncol, 2010, 11, 521)

•  IFCT-GFPC                                                       (Perol M et al. JCO, 2012, 30, 3516)

 

Beva + Erlo (ATLAS)                                        (Johnson BE et al. JCO, 2013, 31, 3926)

    Gefitinib (INFORM)                                       (Zhang L et al. Lancet Oncol, 2012, 13, 466)

Palliative therapy in pre-treated patients

Docetaxel

(Shepherd FA et al. JCO, 2000, 18, 2095; Fossella FV et al. JCO 2000, 18, 2354)

Pemetrexed (non-squamous NSCLC)    

(Hanna N et al. JCO, 2004, 22, 1589)

Erlotinib

(Shepherd FA et al. NEJM, 2005, 353, 123)

Crizotinib in ALK-positive tumors

(Shaw A et al. NEJM, 2013, 368, 2385)

Docetaxel plus nintedanib

(Reck M et al. Lancet Oncol, 2014, 15, 143)

Docetaxel plus ramucirumab

(Garon EB et al. Lancet, 2014, 384, 665)

Afatinib in squamous cell NSCLC   

(Soria J-C et al. Lancet Oncol, online 6 July 2015)

Nivolumab

(Brahmer J et al. NEJM, 2015, 373, 123; Borghaei H et al. NEJM, online 27 Sept 2015)

Docetaxel ± nintedanib: LUME-Lung 1

(Reck M et al. Lancet Oncol, 2014, 15, 143)
 

Docetaxel ± ramucirumab: REVEL

(Garon EB et al. Lancet 2014, 384, 665)
 

 

Afatinib versus erlotinib in squamous cell carcinoma of the lung: LUX-Lung 8

(Soria J-C et al. Lancet Oncol, 2015, online July 6)
 

Immune checkpoint inhibitors in advanced NSCLC

(Helissey C et al. Curr Opin Oncol, 2015, 27, 108)

Anti-CTLA4

•  Ipilimumab

•  Tremelimumab

Anti-PD-1

•  Nivolumab

•  Pembrolizumab

Anti-PD-L1

•  BMS-936559

•  Atezolizumab (MPDL3280A)

•  Tremelimumab (MEDI4736)

•  Avelumab (MSB0010718C)

Others

Nivolumab vs. docetaxel in advanced NSCLC Survival
 

Advanced NSCLC: treatment options (10/2015)