Evolution of 1st Line Treatment for Advanced Non Squamous NSCLC and Current OPtimal Paradigm

Evolution of 1st Line Treatment for Advanced Non Squamous NSCLC and Current OPtimal Paradigm
Tamer El Nahas,MD
Prof. of Clinical Oncology, Cario Univercity
ESMO & ASCO Member
Introduction:
Did some thing really changed in NSCLC?
The answer to this question is surely yes.
Starting with its staging, where new classification of M1a and M1b has been introduced. The choice of chemotherapy has been variously altered from «one size fits all» to be replaced by pathological subtype selection. New molecular drivers and newly discovered gene mutations including EGFR, AIK / EML & K-RAS have been recently of great benefit. There has been a huge jump in the field of new chemotherapy drugs,with acceptance of maintenance treatment. Recent epidemiologic changes have showed that lung cancer is the first cause of death from cancer in the world (both males and females), with an overall increase in its incidence worldwide. In developed countries, there is a slow decrease in the incidence among males, however, the incidence is increasing in femals. The historical subtypes vary according to gender and smoking history.
Among smokers, the incidence of squamous cell cancer is the highest among males, while in females it is more towards Adenocarcinoma However, in non-smokers group,the incidence of adinocarcinoma is the highest among both males and females. Smoking is a very important risk factor, and smoking caesation is always the best tools protection against lung cancer.
NSCLC: stage at diagnosis is often in agvanced stage (stage 4 : 55% of cases), 5 years overall survival is very low,only 1%.
Chemotherapy VS best supportive care in advanced stage NSCLC: Meta-analysis comparing both showed an absolute 1 year benefit of cth over BSC alone by 20 to 29%.
In late go’s, we reacted a ceiling for improved benefit of doublet chemotherapy with 3rd generation agents in advanced NSCLC. The most effective protocol was paclitaxel + carboplatin with a median survival of 8 monthes, and 1 year survival: 36%.
Are platin-free regimens as equivalent as platin-based combinations?
Most new drugs have been already evaluated in combination (taxane + vinorelbine, taxane + gemcitabine, vinorelbine + gemcitabine). Generally platin-free regimens are less toxic and as active as cisplatin based doublets, with no difference in overall survival, but with lower RR and PFS.
Pemetrexed and role of histology in treatment decision:
According to JMDB trial, by
Scaglrotti et al (2008) pemetrexed + cisplatin showed overall survival of 12.6 months in adenocarcinoma to 10.9 months in the arm of gemcitabine + cisplatin.Yet. In squamous cell ca, gemcitabine + cispltin was more superior interms of overall survival. This study introduced pemetrexed as a new leading agent in treatment of lung adenocarcinoma.
What is pemetrexed?
It is a potent inhibitor of (TS), an important enzyme in DNA replication and repair mechanism. TS level correlate with response and survival with TS inhibitors (pemetrexed). Starting from 2008, the factors influencing treatment strategy in NSCLC include tumor histopathology.
Bevacizumab based regimen and its concern:
According to E-4599 phase Ⅲ study, by sandler (2006), addition of beva cizumab to paclitaxel / carboplatin showed an increase in 1 year survival (51% VS 44%) over paclitaxel / carboplatin alone.
Are all CT backbones equally good matches for bevacizumab?
Alesson learned from breast cancer arena, we realized that paclitaxel carbo can be a weaker backbone but a better match for bevacizumab with better results compared to cisplatin / gemzar which is not the ideal backbone for beva.
New question: pemetrexed / cisplatin or bevacizumab /paclitaxel / carboplatin in treatment of a deno ca.?
The answer to this was through a comparative study analyzing survival and safety of both protocols in chemotherapy, naive patients with advanced non-squamous bronchogenic ca. not harboring EGFR mutation, that was published by kader et al on 2013, results of this study showed that cisplatin /pemetrexed regimen provides similar efficacy as bevacizmab / paclitaxel / carboplatine, however with better safety profile
Anti-EGFR treatment:
In late go’s, there were new therapeutic needs in NSCLC there was aneed for improved survival and time to disease progression, as well as, a need for improved quality of life and better treatment toxicity profile.
It was when personalised medicine was first introduced the plan was to identity a driving oncogene, select the best biomarker, choose the appropriate primary end point, and explain the mechanism of resistance. Surprisingly, gene mutation was found in 67% of cases. Most common mutations in adeno ca. were KRAS (28%) & EGFR (13%) genes. This new strategy lead in return to an increase in overall survival in advanced disease NSCLC patients to be: 18 months, these promising results are aided by IPASS study, by mok et al (2009), where the use of a tyrosine kinase inhibitor (anti-EGFR): Gefitinib showed a marked improvement compared to paclitaxel / carboplatin.
EGFR tyrosine kinase Inhibitors:
Things we know: response seems better in patients with:
1- EGFR gene mutation.
2- Females
3- Adenocarcinoma with BAC features.
4- Limited smoking population.
5- Asians.
Things we are trging to find out:
1- Does this correlate to survival?.
2- Are some EGFR mutations more predictive than others ?
3- What is the role of KRAS mutations ?
4- What is the role of EGFR protein expression assessed by IHC ?
5- How to overcome resistance ?
Anti-EMly / Alk treatment :-
anaplastic Lymphoma Kinase (ALK) is an orphan member of the insulin receptor tyrosine Kinase, whose normal function is poorly under stood.
.chromosomal re-arrangement involving the ALK gene serve as potent oncogenic driver and occur in a variety of malagnancy including NSCLC, anaplastic large cell NHL, and inflammatory myofibroblastic tumors
.Crizotinib, an anti ALK gene mutation , that was introduced in clinical trials since 2007, and showed a miraculous response in phase Ⅰ trials that represnted the begining of successful crizotinib story in patients with ALK-positive NSCLC, with objective response rate (ORR) of 57% . Acomparative study by shaw et al (2012), coparing crizotinib verus chemotherapy as .Second line therapy in ALK positive NSCLC patients, revealed better results in crizotinib arm of the study in terms of ORR ratio.
Conclusions : where we are and where we are heading :-
. Realization the lung cancer is quite heterogenouss.
. «one size fits all» era of treatment and drug development is over for lung cancer.
. Tow validated genomic targets
-Mutant EGFR and ALK rearrngement.
-Use in earlier disease and mechanism to overcome drug resistance.
. Rapid pace of pre-clinical discoveres is awaited.
. Finally, goal is to find out and develop effective therapies for all subsets of NSCLC patients.