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\begin{document}

\title{Paradigm shift in the management of metastatic Non-small Cell Lung
Cancer}



\author[1]{Ruby Gupta}%
\author[2]{Melanie  Smalley}%
\author[2]{Nwabundo  Anusim}%
\author[3]{Vishal Jindal}%
\author[4]{Mandeep Singh Rahi}%
\author[5]{Sorab Gupta}%
\author[6]{Sachin Gupta}%
\author[2]{Ishmael  Jaiyesimi}%
\affil[1]{William Beaumont Hospital}%
\affil[2]{William Beaumont Hospital - Royal Oak}%
\affil[3]{William Beaumont Hospitals Corp}%
\affil[4]{Bridgeport Hospital}%
\affil[5]{Bronx-Lebanon Health Care System}%
\affil[6]{Reading Hospital}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: Lung cancer is one of the leading causes of cancer mortality
in the US. The use of precision medicine in the past 10 years has
significantly changed the therapeutic landscape of lung cancer.
Management of advanced non-small cell lung cancer (NSCLC) has
transitioned from a chemotherapeutic approach to targeted treatments and
immunotherapeutic agents. Several tyrosine kinase inhibitors (TKIs) have
been approved for patients with targeted mutations while patients who do
not have driver mutations; immunotherapy has been recently approved as
frontline therapy, which has resulted in marked improvement in overall
survival and added a new tool in our armamentarium. Aims: The purpose of
this review is to highlight recent advancements in diagnostic approach
and management strategies in patients with metastatic NSCLC. Materials
and methods: Published studies included in Medline (via PubMed) and
National Comprehensive Cancer Network Guidelines were reviewed for data
gathering. Conclusion: The use of next generation sequencing has
significantly changed our understanding of molecular oncogenic
mechanisms of lung cancer. These advancements have created a paradigm
shift in the treatment strategies of metastatic lung cancer from
primarily chemotherapeutic approach to increasing use of targeted
therapies and immune check point inhibitors (ICI) leading to better
survival rates and lesser toxicity.%
\end{abstract}%



\sloppy


\emph{Paradigm shift in the management of metastatic Non-small Cell Lung
Cancer}

\textbf{Ruby Gupta\textsuperscript{1}, Melanie
Smalley\textsuperscript{2}, Nwabundo Anusim\textsuperscript{1}, Vishal
Jindal\textsuperscript{1}, Mandeep Singh Rahi\textsuperscript{3}, Sorab
Gupta\textsuperscript{4}, Sachin Gupta\textsuperscript{5} and Ishmael
Jaiyesimi\textsuperscript{1}}

\begin{enumerate}
\tightlist
\item
  William Beaumont Hospital, Department of Hematology and Medical
  Oncology, Royal Oak, Michigan
\item
  William Beaumont Hospital, Department of Internal Medicine, Royal Oak,
  Michigan
\item
  Division of Pulmonary Diseases and Critical Care, Yale-New Haven
  Health Bridgeport Hospital
\item
  BronxCare Hospital, Department of Hematology and Medical Oncology,
  Bronx
\item
  Tower Health Reading Hospital, Department of Internal Medicine,
  Reading
\end{enumerate}

\textbf{Corresponding Author-}

Sorab Gupta

BronxCare Hospital

Department of Hematology and Medical Oncology

Bronx, NY 10457

E- mail- drsorabgupta@gmail.com

\textbf{Abstract}

\emph{Background:}

Lung cancer is one of the leading causes of cancer mortality in the
US\textbf{.} The use of precision medicine in the past 10 years has
significantly changed the therapeutic landscape of lung cancer.
Management of advanced non-small cell lung cancer (NSCLC) has
transitioned from a chemotherapeutic approach~to targeted treatments and
immunotherapeutic agents. Several tyrosine kinase inhibitors (TKIs) have
been approved for patients with targeted mutations while patients who do
not have driver mutations; immunotherapy has been recently approved as
frontline therapy,which has resulted in marked improvement in overall
survival and added a new tool in our armamentarium.

\emph{Aims}\textbf{:}

The purpose of this review is to highlight recent advancements in
diagnostic approach and~management strategies in patients with
metastatic NSCLC.

\emph{Materials and methods}\textbf{:}

A literature search was conducted on Medline (via PubMed) andNational
Comprehensive Cancer Network Guidelines using the keywords ``precision
diagnosis,'' ``advanced non-small cell lung cancer,'' ``target
therapies,'' ``immunotherapy.''

\emph{Conclusion:}

The use of next generation sequencing has significantly changed our
understanding of molecular oncogenic mechanisms of lung cancer. These
advancements have created a paradigm shift in the treatment strategies
of metastatic lung cancer from primarily chemotherapeutic approach to
increasing use of targeted therapies and immunecheckpointinhibitors
(ICI) leading to better survival rates and lesser toxicity.

\textbf{Data gathering method}

Published studies regarding the use of biological therapies in advanced
non-small cell lung cancer were reviewed using Medline (via PubMed) and
National Comprehensive Cancer Network Guidelines for data gathering.

\textbf{Take-home' message for the clinician}

Lung cancer continues to be the leading cause of cancer deaths. The
molecular landscape of lung canceris rapidly evolving leading to a
paradigm shift in the management ofadvanced non-small cell lung cancer.
The new therapeutic regimens are primarily designed to use target
therapies, mainly tyrosine kinase inhibitorsin patients with targeted
mutations and immunotherapies (with or without chemotherapy) in patients
without driver mutations. Both novel treatments have lesser toxicities
and better safety profile compared to chemotherapeutic agents.

\par\null

\textbf{Introduction}

Lung cancer is one of the most frequent and deadly cancers worldwide. In
the United States, approximately 230,000 patients are diagnosed with
lung cancer and it is known to cause over 135,000 deaths annually
{[}1{]}. Tobacco smoking is known to be the most common etiology for
lung cancer accounting for approximately 80\% of the lung cancer cases
in the United States and other countries where smoking is common
{[}2{]}.However, 20\% of lung cancer cases occur in patients who have
never smoked, most commonly in women from East Asia, and has been
associated with environmental exposures such as second-hand smoking,
pollution and occupational carcinogens {[}3-5{]}. In 2010, data from the
National Lung Screening Trial (NLST)showed that screening with low-dose
helical CT scans in highrisk patients as compared with chest radiography
resulted in significant reduction in the rates of both death from lung
cancer (20\%) and death from any cause (6.7\%) {[}6-8{]}.

The understanding of the biology and oncogenic mechanisms in lung cancer
has greatly expanded in the last 20 years. This has led to the
development of new biomarker-targeted therapies andimmune checkpoint
inhibitors, with or without cytotoxic therapy regimens,for use in
patients without targetable mutations.In an exploratory analysis
conducted by Lung cancer mutation consortium, nearly 64\% of 1007
patients with advanced lung adenocarcinoma were found to have targetable
oncogenic drivers. Patients with driver mutations who received targeted
therapies were found to have longer overall survival (OS) as compared to
those with targetable mutation who did not receive targeted treatments
or those without driver mutations (median survival, 3.5 years vs. 2.4
years and 2.1 years, respectively). {[}9{]} In the future, ongoing
efforts to improve precision diagnosis by determining additional novel
molecular markers and targeted therapies will continue to broaden the
patient spectrum with advanced NSCLC patients who can benefit from these
treatments and further improve clinical outcomes.

Since histologic features allow subtyping and molecular analysis of lung
cancers and determine the major treatment options, a pathological
diagnosis is essential.

There are various histological subtypes of NSCLC with adenocarcinoma
(60\%) being the most common type followed by squamous cell carcinoma
(15\%). NSCLC favoring adenocarcinoma is characterized by IHC staining
positive for thyroid transcription factor 1 and cytokeratin 7 and
negative for small cell cancer markers. NSCLC favoring squamous cell
carcinoma is characterized by tumor markers negative for adenocarcinoma
and positive for p63, cytokeratin 5, or cytokeratin 6. The tumor is
classified as NSCLC, not otherwise specified (NOS) if all the above
markers are negative. {[}10{]}.

In this review, we provide an overview of the recent advances made in
understanding the disease biology, mechanisms of tumor progression and
multimodal treatment of metastatic NSCLC.

\textbf{Molecular characteristics of lung cancer}

Lung cancer is a molecularly heterogeneous disease, and several forms of
genomic instability can drive its development.A recent report on whole
exomegenomic sequencing of 100 NSCLC tumor samples revealed that besides
clonal driver mutations, other processes such as chromosomal
instability, genome duplications and subclonal mutations cause genetic
heterogeneity, all of which have an influence on prognosis {[}11{]}.
Understanding the biology and molecular characteristics of this disease
have been crucial for the development of modern treatment strategies in
patients with lung cancer.

The molecular analysis of lung cancers has shown thatEGFR and KRAS and
the tumor suppressor genes TP53, KEAP1, STK11 and NF1 are the most
commonly mutated genes in lung adenocarcinoma, while in squamous cell
lung cancer are tumor suppressor gene TP53, which is present in more
than 90\% of tumors, and CDKN2A are the most commonly mutated
genes{[}12{]}. Actionable mutations in receptor tyrosine kinases are
rarely observed in squamous cell lung cancers (SCLC) even though EGFR
amplification may be found in them {[}13{]}. Mutations in KRAS and EGFR
genes when detected are usually present in the founder clones,
indicating their roles in tumor initiation and can be targets for
therapeutic intervention, while mutations in tumor protein TP53 are
commonly observed with advancing grade, suggesting a role during tumor
progression {[}14{]}.KRAS and EGFR are mutually exclusive but when they
coexist, KRAS mutation can confer resistance to EGFR inhibitors
{[}14{]}.

The genomic profile of smokers is markedly distinct from that of
non-smokers {[}12,15{]}. Non-smokers have predominant transversionof
cytosine to thymine, harbor tumors that have a lower than average
mutation load, and have a higher prevalence ofoncogenic drivers such as
EGFR mutations, anaplastic lymphoma kinase (ALK) rearrangements , ROS
proto-oncogene receptor tyrosine kinase 1 (ROS1) , BRAF V600 E
mutations, and neurotrophic receptor tyrosine kinase (NTRK) gene
fusions;tumors from smokers contain higher mutation frequency,
predominantly cytosine to adenine nucleotide transversions, and
non-actionable mutations such as KRAS and TP53 {[}9,12,15{]}.

An oncogenic driver identified relatively recently in NSCLC is human
epidermal growth factor receptor (HER2, also known as ERBB2),a member of
the EGFR receptor tyrosine kinase family,which has been added to the
growing list of actionable targets {[}16,17{]}.Early studies observed
HER2 overexpression in approximately 1\% to 2\% of lung cancer cases,
whereas results from more current studies show a range of approximately
6\% to 30\%{[}18{]}.Data from tumor models and patients expressing HER2
mutations suggest that they tend to be insensitive to EGFR tyrosine
kinase inhibitors (TKIs), suggesting the need for specific HER2-directed
therapies for these patients. Many clinical trials are being conducted
to identify effective and safe targeted treatment for metastatic
HER2-mutated NSCLC patients {[}19{]}.

Due to increasing knowledge of tumor heterogeneity, molecular testing is
now performed at the time of metastatic non-small cell lung cancer
diagnosis to identify gene mutations or rearrangements for which there
are targeted therapies. The molecular targets of non-small cell lung
cancer described above are shown in Figure 1.

The use of immune checkpoint inhibitors has become the standard of care
for patients with advanced NSCLC. The only predictive biomarker
currently available to guide treatment with immunotherapy is programmed
death- ligand 1(PD-L1) protein. {[}19{]} Studies have shown that PD-L1
tumor proportion score (TPS) measured by immunohistochemical assay is a
better predictor of response to immunotherapy as compared to programmed
cell death 1 (PD-1). Therefore it is recommended that all patients with
advanced NSCLC should get testing for PD-L1 TPS.{[}20{]} A PD-L1 TPS
score \textgreater{}50\% is required for first line treatment with
pembrolizumab while patients who have progressed on previous treatment
can receive immunotherapy for~ PD-L1~ negative tumors. {[}21{]} In
patients with PD-L1 negative tumors, the selection of treatment may be
based on tumor mutational burden, disease volume and performance
status.{[}21{]} The research now is focused on finding a new predictive
biomarker for immunotherapy so that it can guide optimal treatment
benefit in patients.

\textbf{Therapeutic strategiesfor advanced NSCLC}

\textbf{Targeted Therapy}

The management of lung cancer has been transformed by the advent of next
generation sequencing leading to identification of therapeutic targets
resulting in better clinical outcomes compared to patients with absence
of molecular targets. {[}9{]} Therefore molecular testing for treatable
oncogenic alterations should be implemented as an essential part of
diagnostic testing before deciding treatment plan for a patient with
newly diagnosed NSCLC.{[}22,23{]}

\textbf{EGFR- mutant advanced NSCLC}

The incidence of somatic EGFR mutation in advanced NSCLC is
approximately 20\% in Caucasian patients, but higher incidence rates of
about 48\% have been found among patients of East Asian ethnicity
{[}24{]}. The incidence of mutation also correlates with histologic type
of NSCLC, sex and age of patient and smoking history. {[}25{]}EGFR
belongs to a receptor kinase family that also includes human HER2(ERBB3)
and HER3 (ERBB4) {[}26{]}. The most commonly seen mutations are EGFR
exon 19 deletion or missense point mutation on exon 21 (EGFR
L858R),associated with increased sensitivity to EGFR tyrosine kinase
inhibitors (TKI) {[}26{]}.First-generation EGFR TKIs, including
gefitinib and erlotinib, resulted inhigher objective response rates
(ORRs) and progression-free survival (PFS) compared to cytotoxic therapy
in previously untreated patients with EGFR mutations {[}27-31{]}. In a
meta-analysis of randomized trials of the EGFR tyrosine kinase
inhibitors gefitinib, erlotinib and afatinib, significant improvement
was seen in ORR and PFS, as compared with first-line chemotherapy (PFS
9.6-13.1 months versus4.6-6.9 months; (HR)for progression or death,
0.37; 95\% confidence interval (CI), 0.32 to 0.41; p\textless{}0.001)
{[}32{]}.

In contrast to the first-generation EGFR TKIs gefitinib and erlotinib,
which are reversible competitive ATP inhibitors targeting only EGFR,
second-generation inhibitors including afatinib and dacomitinib are
irreversible inhibitors that also target HER2 and HER4.
Second-generation TKIsafatinib and dacomitinibdemonstrated improved PFS
when compared to first generation TKI gefitinib{[}33, 34{]}. Despite
impressive initial responses to both first- and second-generation EGFR
TKIs, most patients experience disease progression after 9-12 months of
treatment, indicating the frequent emergence of resistance to these
agents.

Many mechanisms of resistance have been known by which first and second
generation TKIs become ineffective in patients taking it. The most
common is a second mutation in exon 20, with a threonine-to-methionine
substitution on codon 790 (T790M). {[}35{]} This eventually causes
resistance either due to tyrosine kinase domain having increased
affinity for ATP or from steric hindrance. {[}35 {]} Other mechanisms of
acquired resistance include SCLC transformation, mutations in
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit-alpha
(PIK3CA) , MET or BRAF and~ amplifications in HER 2. {[}36{]} Nearly
60\% of patients develop resistance after first- or second-generation
EGFR TKI due to T790M mutation and third generation EGFR TKI can
specifically overcome it. {[}36{]}Therefore, it becomes important to
repeat next generation sequencing at the time of disease progression.
{[}36{]} Osimertinib, a third generation irreversible EGFR TKI targeting
T790M mutation, binds covalently to cysteine on codon 797, overcoming
the resistance. ~{[}37, 38{]}Osimertinib has now been FDA approved as
upfront treatment for advanced NSCLC patients with exon 19 deletion or
L858R sensitizing mutation replacing first and second generation TKIs.
{[}39{]}This is based on efficacy and safety data results of the FLAURA
trial.~ In this double-blind phase III randomized control study, 556
treatment naive EGFR mutation-positive advanced NSCLC patients were
assigned to either receive osimertinib or standard EGFR-TKI (gefitinib
or erlotinib) in 1:1 ratio. Osimertinib was found to have superior
efficacy with median PFS 18.9 months vs 10.2 months ; p\textless{}0.001
and median OS 38.6 vs 31.8 months;p= 0.046 compared with erlotinib and
gefitinib. Some other favorable outcomes with osimertinib were lower
rates and grades of side-effects, fewer cases of central nervous system
progression and improved post-progression outcomes.{[}40{]}

Unfortunately, patients eventually progress on osimertinib as well
indicating resistance to the drug. One of the mechanisms suggested is
acquisition of C797S mutation which along with L858R sensitizing
mutation leads to resistance to third generation EGFR TKIs. {[}41{]}
Patients with mutation in T790M, C797S and sensitizing mutations are
called triple mutants and it causes resistance to all three generations
of EGFR TKIs.{[}42{]} In order to overcome resistance caused by triple
mutation, various strategies are being tried. Cetuximab, an anti-EGFR
monoclonal antibody, is being used along with allosteric inhibitor
EAI045 in patients with L858-R sensitizing mutation and an ALK
inhibitor, brigatinib, known to have activity against EGFR mutations, in
tumors with exon 19 deletion. {[}43,44{]}

Combinatorial approaches in the treatment of metastatic lung
adenocarcinoma have shown promise. The combination of ramucirumab plus
erlotinibwas approved by FDA for upfront treatment of patients with
metastatic NSCLC whose tumors have EGFR exon 19 deletion or exon 21
(L858R) substitution mutation, based on a phase III multinational,
randomized, double-blind, placebo-controlled trial, the RELAY
trial{[}45{]}. A 1:1 randomization of 449 patients was done to receive
oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10
mg/kg) or matching placebo once every 2 weeks. Ramucirumab plus
erlotinib group showed significantly longer PFS compared to erlotinib
plus placebo (19.4 months; 95\% CI, 15.4--21.6 versus 12.4 months;95\%
CI,11.0--13.5, respectively) with a HR of 0.59 (95\% CI 0.46--0.76;
p\textless{}0.0001) {[}45{]}.

\textbf{Future directions in the treatment of patients with EGFR mutated
advanced NSCLC}

Clinical trials using combinatorial approaches that have shown positive
results are described below.

In an ongoing phase I/II study in patients withmetastatic EGFR-mutated
(L858R or del19) NSCLC, 27 patients were given osimertinib plus
gefitinib for treatment na\selectlanguage{ngerman}ïve patients{[}46{]}. The maximum tolerated
dose was 80 mg osimertinib plus 250 mg gefitinib orally daily. 81.5\%
patients were able to complete\selectlanguage{english}[?] six cycles combination therapy (1 was
discontinued for progressive disease, 4 for side-effects) with ORR of
85.2\% (95\% CI, 67.5\%-94.1\%).Nearly 82.4\% of treated patients were
found to have undetectable plasma EGFR at 2 weeks of treatment. The
median progression- free survival was not reached (NR) at 14.8 months
follow up {[}46{]}.

In the phase II portion of a single-center phase I/II trial, the
combination of first-line osimertinib plus bevacizumabresulted in a
significantly improved 1-year PFS of76\%as compared to historical rate
of 51\%{[}47{]}.

In NEJ026, a phase III trial comparing bevacizumab plus erlotinib to
monotherapy with erlotinibfor EGFR-mutated NSCLC, the combination
regimen was associated with significantly superior PFS compared to
single agent erlotinib{[}48{]}. At the time of interim analysis (12.4
months), patients in the erlotinib plus bevacizumab group had
significantly better median PFS of 16.9 months (95\% CI, 14.2-21.0)
compared with 13.3 months (95\% CI, 11.1-15.3) for patients in the
erlotinib group (HR 0.605; 95\% CI, 0.417-0.877;
p=0.016){[}48{]}.Updated results of this trial presented at ASCO 2020
showed median OS with bevacizumab plus erlotinibof 50.7 months (95\% CI,
37.3-NR) compared to 46.2 months (95\% CI, 38.2-NR) with erlotinib alone
(HR, 1.00; 95\% CI, 0.68-1.48). Bevacizumab plus erlotinib were also
found to have higher median survival time between enrollment and
progression of disease with second line treatment ( 28.6 months compared
to 24.3 months ) with erlotinib alone

{[}49{]}.

\textbf{ALK Translocations}

Nearly 5\% of NSCLC patients are found to have overexpression of ALK
protein caused by translocations of ALK. The first target drug that was
associated with improved ORR and median PFS in these patients was
crizotinib, which is an inhibitor of dual receptor tyrosine kinases
including ALK and MET. In two randomized phase III trials involving
patients with NSCLC and ALK alterations, crizotinib had superior
efficacy as compared with chemotherapy in previously treated patients
(median PFS, 7.7 vs. 3.0 months) {[}50{]}, as well as in previously
untreated patients in the PROFILE 1014 trial (median PFS, 10.9 vs. 7.0
months) {[}51{]}. ALK-TKIs became the standard of care as initial
therapy based on the above phase III trials. This also highlighted the
importance of doing next generation sequencing in all patients at the
time of diagnosis of metastatic NSCLC. In the four-year follow up of the
final OS analysis of PROFILE 1014 trial in 2018, median OS for
crizotinibwas NR (95\% CI, 45.8 months - NR) versus 47.5 months with
chemotherapy (95\% CI, 32.2-NR) {[}52{]} showing superior efficacy of
crizotinib over chemotherapy.

Soon it became evident that patients with ALK translocations treated
with crizotinib became resistant to the treatment and further analysis
showed several complex escape mechanisms and secondary mutations as
mechanisms of resistance {[}53{]}. This led to clinical trials with
newer second generation ALK-TKIs (alectinib, ceritinib and brigatinib)
that were more potent and effective in overcoming resistance to
crizotinib as evidenced by radiographic responses among patients with
ALK mutations who progressed on crizotinib{[}54-56{]}.Response rates of
38\%-56\% have been reported with a median PFS of 5.7-8.0 months when
second-generation ALK tyrosine kinase inhibitors such as ceritinib or
alectinib were given to patients with ALK translocations after the
failure of crizotinib therapy. Furthermore, these drugs show efficacy in
patients with brain metastases (brain response rate, 33-57\%), which is
of clinical importance for this group of patients.

In untreated patients with ALK alterations, ceritinib proved superior to
chemotherapy in the ASCEND-4 trial (median PFS, 16.6 vs. 8.1 months; HR
for progression or death, 0.55; 95\% CI, 0.42-0.73; p\textless{}0.001)
{[}57{]}. Alectinibwas superior to crizotinib in the Japanese J-ALEX
trial (PFSNR vs. 10.2 months; HR for progression or death, 0.34; 95\%
CI, 0.17-0.70; p\textless{}0.001) {[}58{]} and in the ALEX trial (PFSNR
vs. 11.1 months; HR for progression or death, 0.47; 95\% CI, 0.34-0.65;
p\textless{}0.001) {[}59{]}. Another randomized study showed increased
ORR and median PFS for alectinib compared to crizotinib in patients with
previously untreated ALK-positive NSCLC, establishing alectinib as a
first-line treatment option. Significantly higher median PFS was
reported with alectinib compared to crizotinib (34.8 months versus 10.9
months, respectively) in an updated data on the ALEX trialin 2019
{[}60{]}. Alectinibwas found to have much better toxicity profile
compared tocrizotinibdespite longer treatment duration with
alectinib{[}60{]}.In ALTA-1L study brigatinibshowed improved efficacy
compared tocrizotinib (N\selectlanguage{english} =\selectlanguage{english} 275; 12-month Kaplan-Meier PFS rate, 67\%
versus 43\%; \emph{P} \selectlanguage{english} \textless{}\selectlanguage{english} .001), with fewer episodes of
progressive disease in the CNS {[}61{]}. Updated data after more than 2
years of follow-up fromALTA-1L showed that the risk of disease
progression or death was reduced by brigatinib by 76\% (HR, 0.24; 95\%
CI, 0.12--0.45), in newly diagnosed patients who had CNS involvement at
the time of enrollment. Brigatinibwas also associated with 57\%
reduction in the risk of disease progression or death in all patients
{[}61{]}.Alectinib was FDA approved on Nov 6, 2017 and brigatinibon May
22, as initial therapy for patients with ALK-positive NSCLC.

The emergence of drug resistance was unfortunately seen with second
generation TKIs, alectinib and brigatinib as well despite a prolonged
median disease-free period of 2 years. This led to further trials
looking into third generation ALK inhibitor, loratinib for treatment of
ALK-positive NSCLC patients who had progressed on two prior ALK-TKI.
Loratinib finally got FDA approval on 2nd November 2018 for second- or
third-line treatment of ALK-positive metastatic NSCLC based on a
multiple-cohort phase 2 trial.{[}62{]}

This has led to median survival of nearly 5 years among patients with
ALK-positive NSCLC treated with crizotinib followed by a second or third
generation TKI.

\textbf{ROS1-Rearranged NSCLC~}

Chromosomal rearrangements of the gene encoding ROS1 have been found in
approximately 1\% of patients with NSCLC {[}63{]}. Due to considerable
homology between the kinase domains of ROS1 and ALK, drugs used to treat
ALK-positive tumors including crizotinib{[}63{]}, ceritinib {[}64{]} and
lorlatinib {[}65{]} have also shown marked activity in ROS1-positive
tumors. Crizotinib was found to have a response rate of 72\% and median
PFS of 19 months in 50 patients with NSCLC and ROS1 rearrangement
{[}63{]}. Repotrectinib (TPX-0005) may be an effective therapeutic
option for patients with NTRK1--3, ROS1 or ALK-rearranged advanced NSCLC
who have progressed on earlier-generation TKIs as it is known to
overcome resistance due to acquired mutations involving NTRK 1-3, ROS1
and ALK {[}66{]}.Cabozantinib has also demonstrated anti-ROS1 activity
in the second-line setting, including activity against G2032R.Most
agents demonstrated good tolerability, with safety and efficacy data
that are being confirmed in ongoing clinical trials, except cabozantinib
which isassociated with higher toxicity, and it is therefore limited as
a therapeutic agent for some patients.

\textbf{BRAF-Mutant NSCLC~}

BRAF mutations have been identified in 2\% of patients with NSCLC, half
of whom have a BRAF V600E mutation. In these patients, the response rate
was 63.2\%, and median PFS was 9.7 months after treatment with a
combination of the BRAF inhibitor dabrafenib and the MEK inhibitor
trametinib{[}68{]}.A response rate of 42\% and median PFS of 7.3 months
were reported after treatment with vemurafenib, another BRAF inhibitor
{[}69{]}.These data strongly recommend using targeted therapy to
treating patients with BRAF-mutant lung cancer for better clinical
outcomes .

\textbf{MET exon 14-skipping mutations}

Somatic mutations that affect MET exon 14, which contains the Y1003
residue required for ubiquitin-mediated degradation, lead to increased
MET stability and prolonged signaling from hepatocyte growth factor
stimulation {[}70{]}. On May 6, 2020, an accelerated approval to
capmatinibwas granted by FDA for adult patients with metastatic NSCLC
withMET exon 14-skipping mutations. This approval was based on the
GEOMETRY mono-1trial, a multicenter, nonrandomized, open-label,
multicohort study in which 97 patients with metastatic NSCLC with
confirmed MET exon 14-skipping mutationswere treated with
capmatinib{[}71{]}. The ORR was much higher, 68\% among the 28
treatment-naive patients, with a response duration of 12.6 months (95\%
CI, 5.5--25.3) compared to ORR of 41\% among the 69 previously treated
patients, with a response duration of 9.7 months (95\% CI, 5.5--13.0)
{[}71{]}.

The single-arm, international phase II VISION trial presented at ASCO
2020 has also shown tepotinib to have activity in patients withMET exon
14-skipping mutations. After nine months follow-up, the primary efficacy
population of 99 patients had a 46.5\% ORR, with duration of response of
11.1 months {[}72{]}.

\textbf{Rearrangements in RET}

RET gene rearrangements can cause tumorigenesis in approximately 1 to
2\% of patients with NSCLC {[}73{]}. Multiple RET targeting TKIs that
have shown clinical efficacy in patients with RET rearrangements are
available in the market. Cabozantinib and Vendatinib have shown modest
clinical efficacy with ORR of 28\% and 18\% and PFS of 5.5 months and
4.5 months respectively. {[}74, 75{]}

In another multicenter, multi-cohort clinical trial LIBRETTO-001,
efficacy of selpercatinib was evaluated in patients with RET fusion
positive NSCLC.In this study, 105 adult patients previously treated with
platinum chemotherapy were treated with selpercatinibshowed ORR of 64\%
with 81\% having responses lasting 6 months or longer. Selpercatinib was
also given to 39 patients who never received systemic treatment before
and was found to show ORR of 85\% with 58\% patients having responses
lasting 6 months or greater. {[}76{]} Based on this trial, FDA granted
accelerated approval to selpercatinib in metastatic RET fusion-positive
NSCLC on May 8, 2020.

\textbf{Fusions of the neurotrophic tyrosine receptor kinase (NTRK)
genes 1, 2 and 3}

NTRK fusions occur in many tumor types and are known to occur in less
than 1\% of NSCLC. The oral TRK inhibitor FDA approved in first line or
subsequent setting for NSCLC patients harboring fusions in NTRK genes is
Larotrectinib.

The efficacy of Larotrectinib was tested in phase I/II clinical trial
that enrolled 55 patients with NTRK gene rearrangements regardless of
cancer type. The ORR was 75\% (95\% CI, 61 to 85). At 1 year, PFS was
55\% with 71\% having ongoing responses. This led to the FDA approval of
larotrectinib for NTRK-altered cancers as ``tumor -agnostic'' indication
based on actionable genomic insights {[}77{]}.

\textbf{Mutations in HER2}

Approximately 2\% of patients with NSCLC are found to harbor HER 2 exon-
20- insertion mutation that is detected using PCR or NGS. HER 2-
targeted antibody drug conjugate, ado-trastuzumab emtansine has shown
modest clinical efficacy in these patients. {[}78{]}

In a phase II clinical trial, 18 patients with HER 2 mutated NSCLC were
treated with ado-trastuzumab emtansine after a median of 2 prior line of
systemic therapy. These patients were found to have ORR of 44\%, median
PFS of 5 months and median duration of response was 4 months, suggesting
that we can offer this treatment off label in patients HER2-positive
NSCLC refractory to other standard available therapies. {[}78{]}

In an ongoing, multicenter phase II study DESTINY-Lung01, 42 patients
with non-squamous cell lung cancerwith HER2-activating mutation were
administered ~trastuzumab~deruxtecan. The ORR among these 42 patients
was 62 percent with estimated median PFS of 14 months. {[}79{]}

Given that these two drugs are FDA approved for other HER2- positive
malignancies, we can offer this treatment off label in patients with
HER2-positive NSCLC refractory to other standard available therapies.

\textbf{Immunotherapy in Advanced NSCLC~}

The targeted therapies described above have significantly changed the
outlook for those patients with identifiable mutations. However, nearly
70\% of patients with advanced NSCLC do not have driver genetic
mutations, and immune checkpoint inhibitors are the mainstay of
treatment for these patients {[}80{]}. These inhibitors target either
programmed cell death protein 1 (PD-1) or programmed cell death ligand 1
(PD-L1).PD-1 is a transmembrane protein that is expressed on T cells, B
cells and Natural Killer cells and inhibits PD-L1 when it binds
{[}81{]}.~As PD-L1 is expressed on many tumor cells, the interaction of
PD-1 and PD-L1 can be exploited in cancer treatment {[}80{]}. The PD-1
inhibitors pembrolizumab and nivolumab{[}80{]}and the PD-L1 inhibitors
atezolizumab, avelumab, and durvalumab{[}80{]} can be used alone or in
combination with chemotherapy based on individual patient factors, and
have been shown to improve OS in patients with advanced NSCLC.

In patients with NSCLC who have not received chemotherapy, treatment
decisions are based on the amount of PD-L1 expression. If PD-L1
expression is high (50\% or greater), pembrolizumab can be used as
monotherapy if patients do not have rapidly progressing disease.This is
based on the KEYNOTE-024 trial of 305 patients with high PD-L1
expression who were assigned pembrolizumab monotherapy versus
platinum-doublet therapy {[}82{]}. The results of this study showed
prolonged PFS (10.3 versus 6 months) and higher ORR (45\% versus 28\%)
in the pembrolizumab group compared to chemotherapy {[}82{]}. The
pembrolizumab group also had a lower number of severe adverse events
{[}82{]}. An update on KEYNOTE-024 presented 3 years later showed a
median OS with pembrolizumab of 30.0 months (95\% CI, 18.3-NR) versus
14.2 months (95\% CI, 9.8-19.0) with chemotherapy (HR, 0.63; 95\% CI,
0.47-0.86) {[}83{]}.No studies have been performed to directly compare
pembrolizumab monotherapy versus chemotherapy plus pembrolizumab in
patients without rapidly progressing disease. For patients with high
PD-L1 expression and rapidly progressing disease, pembrolizumab with
chemotherapy is recommended based on a meta-analysis of five studies
with either pemborlizumab monotherapy or pemborlizumab in combination
with chemotherapy{[}84{]}. Again, no randomized controlled trials have
directly studied pembrolizumab monotherapy versus pembrolizumabplus
chemotherapy in this patient group.

If PD-L1 expression is less than 50\% and patients are treatment-naive,
pembrolizumab with chemotherapy is the first line treatment option for
both squamous and nonsquamous NSCLC. There have been two large
randomized control trials comparing chemotherapy with and without
pembrolizumab in patients with nonsquamous NSCLC, the KEYNOTE-021 and
KEYNOTE-189 trials{[}85,86{]}.KEYNOTE-021 randomized 123 patients to
chemotherapy with and without pembrolizumab. The group with
pembrolizumab had higher ORR (55\% versus 29\%) and PFS (13 versus 6
months) {[}85{]}.KEYNOTE-189 studied 616 patients with nonsquamous
NSCLC. These patients either received chemotherapy alone or with
pembrolizumab, and patients receiving chemotherapy alone
hadpembrolizumab added with disease progression. Pembrolizumabtreatment
resulted in an improved PFS of 8.8 versus 4.9 months. There was also
improved 12-month OS in the pembrolizumabpluschemotherapy versus
chemotherapy alone (69\% versus 49\%){[}86{]}. A similar study was
performed in patients with squamous NSCLC, KEYNOTE-407, where 559
patients were randomized to either chemotherapy with pembrolizumab or
chemotherapy with placebo. The addition of pembrolizumabagainresulted in
improved OS and PFS{[}87{]}.

The anti-PD-L1 antibodyatezolizumab may provide an alternative therapy
to pembrolizumab and chemotherapy, and has been investigated in
combination with chemotherapy in patients with nonsquamous NSCLC. The
IMpower 150 trial assigned 1202 patients with advanced NSCLC to three
groups: chemotherapy with atezolizumab, chemotherapy with atezolizumab
plus bevacizumab, or chemotherapy with bevacizumab. Those receiving
chemotherapy with atezolizumab plus bevacizumab had better PFS and OS
(19.2 versus 14.7 months in the chemotherapy/bevacizumab group){[}88{]}.
The IMpower 130 and IMpower 132 trials also demonstrated improved OS and
PFS with the addition of atezolizumab to chemotherapy in patients with
nonsquamous NSCL. {[}89,90{]}. The addition of atezolizumab has also
been studied in squamous NSCLC but did not demonstrate any OS benefit,
so is not recommended for these patients {[}91{]}.

Immunoglobulin G4 monoclonal antagonist antibodies such as nivolumabcan
also play a role in the treatment of NSCLC. Cytotoxic T-lymphocyte
antigen-4 (CTLA-4) is a negative regulator of T cell activation and is
implicated in immune surveillance of cancer {[}92{]}.Ipilimumab is a
monoclonal antibody directed against CTLA-4 that can be used in
combination with nivolumab as an alternative to pembrolizumab and
chemotherapy in patients with low PD-L1 expression {[}92{]}.Nivolumab
was studied as monotherapy in the CheckMate 026 trial of 541 patients
with advanced, untreated PD-L1 positive tumors but did not result in
prolonged PFS or OS{[}93{]},while the combination of nivolumab and
ipilimumab used in the CheckMate 227 trial has shown improved OS
compared to chemotherapy (17.1 versus 13.9 months) {[}94{]}.The
combination of nivolumab plus ipilimumab has also been shown to be
beneficial in patients with high PD-L1 expression, though pembrolizumab
remains the preferred treatment.

In another study presented at ASCO 2020, data from CheckMate9LA, a phase
III trial evaluating nivolumab plus low-dose ipilimumab combined with
chemotherapy showed superior OS compared to chemotherapy alone in the
first line NSCLC treatment. Nivolumab plus ipilimumab combined with 2
cycles of platinum-doublet chemotherapy demonstrated superior OS versus
chemotherapy alone (HR, 0.69; 96.71\% CI, 0.55-0.87; p=0.0006),
regardless of PD-L1 expression or tumor histology {[}95{]}.

Although immunotherapy has been shown to impart a statistically
significant survival benefit and drastically changed the current
treatment of NSCLC, the survival difference is generally months over
that achieved with conventional therapy. Therefore, it is imperative to
discuss all of the risks and benefits of immunotherapy with a patient in
order to best suit that individual's goals of care. Table 4 lists the
ongoing clinical trials of immunotherapy in advanced NSCLC. Completion
of these trials will potentially result in better treatment options for
the future.

\textbf{Conclusion}

In summary, precision medicine has helped with better understanding of
the biology and oncogenic mechanisms of lung cancer. This has led to a
new foundation of rationally designed therapeutic regimens including
targeted and immunotherapy, thus expanding the therapeutic landscape of
lung cancer. These regimens have high efficacy and manageable toxicity
profiles, which in turn has led to improved survival. With these new
advancements, we are touching new horizons in lung cancer treatment and
in near future it is expected that chemotherapy will not be commonly
used and lung cancer patients will have longer and better quality of
life.

\textbf{Acknowledgement}

None to declare

\textbf{Financial Disclosure or Funding}

No Funding was required

\textbf{Conflict of Interest}

None

\textbf{Author Contributions}

Ruby Gupta: manuscript idea, research, writing. Melanie Smalley:
writing, editing, NwabundoAnusim: review, editing. Vishal Jindal:
review, editing, Mandeep Singh Rahi: revision, editing. Sachin Gupta: :
revision, editing, Sorab Gupta: revision, editing. Ishmael Jaiyesimi:
editing.

\textbf{Data Availability}

The authors declare that data supporting the findings of this study are
available within

the article.

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\end{enumerate}

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