Targeted therapy for NSCLC

Molecular Markers and Targeted Therapies in the Management of Non-Small Cell Lung Cancer

There are two categories of biomarkers for NSCLC : PD-L1 which is expressed in approximately 1/3 of patients, and is important in those without molecular drivers and mutations in gene rearrangements, which are the objects of targeted therapies.

Approximately 30% of lung cancers can be treated successfully with molecular-targeted therapies, which often yield higher response rates than chemotherapy.

Patients with the molecular alteration should be directed toward targeted. therapy is the first line of treatment.

Patients without a molecular driver and who,have a high PD-L1 expression are typically started on an immune checkpoint inhibitor, alone, or in combination with chemotherapy.

For patients without a driver oncogene, and no to some PD-L1 expression typically chemotherapy is recommended plus an immune checkpoint inhibitor.

The US Food and Drug Administration has already approved treatments specifically targeting EGFR, ALK, ROS1, RET, KRAS G12C  and non KRAS G12C, MET exon, HER2, BRAF  gene mutations or fusions.

Mutations of the epidermal growth factor receptor (EGFR) gene as an oncogenic driver confers sensitivity to small molecule tyrosine kinase inhibitors (TKIs) targeting EGFR.

ALK observed in 5 to 7% of patients, EGFR in 10 to 20%, BRAF in 2 to 5%, METex14 3%, RET1 to 2%, KRAS G12 C 13%, ROS1 1 to 3%, ERBB 1-4% and NTRK 1/2/3 0.2%.

KRAS or RAS mutations occur approximately 28% of patients with NSCLC.

Response rates are approximately 40% in phase 2 trials with the oral drugs Sotorasib  and adagrasib and second line options for patients with KRASG 12 C mutation positive metastatic NSCLC.

Following the discovery of EGFR mutations, rearrangements of the anaplastic lymphoma kinase (ALK) gene7 and ROS1 gene8 were identified as targetable driver mutations in NSCLC.

The frequency of both rearrangements is lower than that of EGFR mutations.

Immune checkpoint inhibitors have limited efficacy in patients with EGFR mutations and can result in increased toxicities in patients who receive immune checkpoint inhibitors followed by a targeted tyrosine kinase inhibitor.

BRAF V600E mutation has been identified in NSCLC.

MET exon 14 mutations or high level amplification, HER2 and RET are emerging biomarkers.

MET exon 14 alteration is identified approximately 4% of patients with metastatic NSCLC.

RET fusions occur in 1.3% of patients and agents selpercatinib and pralserinib are available with clear efficacy.

Patients with MET exon 14 alterations tend to be older and have unusual histology:Capmatinib and tepotinib have a response rates in the 40s with NSCLC.

Identifying a distinct molecular subset of NSCLC patients is critical in treatment.

Currently, molecular testing is mandatory in all stage IV patients with non-squamous cell carcinoma, as a preponderance of patients with driver mutations have this histology subtype.

For squamous cell carcinoma, molecular testing should be considered if the biopsy specimen is small, there is mixed histology, or the patient is a nonsmoker.

Techniques utilized in detecting these genetic alterations:

EGFR mutation can be detected by polymerase chain reaction (PCR).

ALK or ROS1 rearrangement can be detected by fluorescence in-situ hybridization (FISH), and immunohistochemistry (IHC) can also be used to detect ALK rearrangement.

Current guideline is to use comprehensive genomic profiling to capture all the potential molecular targets simultaneously instead of running stepwise tests just for EGFR, ALK, and ROS1, BRAF V600E mutation, MET exon 14 skipping mutation, RET rearrangements, and HER2 mutations are among the emergent genetic alterations with various responses to targeted therapy.

Approximately 2 to 3% of NSCLC have HER2 activating mutations that can be targeted with fam-trastuzumab Deruxetan.

The Lung Cancer Mutation Consortium in the United States demonstrated that the median survival of patients without driver mutations, with drivers mutations but not treated with targeted therapy, and with driver mutations and treated with targeted therapy was 2.08 years, 2.38 years, and 3.49 years, respectively.

The French Cooperative Thoracic Intergroup-French National Cancer Institute demonstrated that the median survival for patients with driver mutations versus those without driver mutations was 16.5 months versus 11.8 months.

The Spanish Lung Cancer Group demonstrated that the overall survival (OS) for patients with EGFR mutations treated with erlotinib was 27 months.

Among EGFR mutant NSCLC, 79% have EGFR in mutations exon 19 deletion and e on 21, 15% have atypical EGFR mutations at 6% have EGFR exon 20 insertions.

Afatinib and osimertinib are preferred first line treatment options for atypical EGFR mutations.

EGFR exon 20 insertions are seen in one percent of patients with NSCLC  and have a better prognosis compared with tumors that lack a targetable  oncogene, but a worst prognosis compared with tumors with classic EGFR mutations.

Therapies that target exon 20 EGFR  insertions  are amivantamab and monocertinib.

The 2 most common EGFR mutations are deletions in exon 19 and substitution of arginine for leucine in exon 21 (L858R).

These mutations are found in approximately 45% and 40% of patients with EGFR mutations, respectively.

Both mutations are sensitive to EGFR TKIs.

The benefit may be greater in patients with exon 19 deletions as compared to exon 21 L858R substitution.

EGFR mutations are found in approximately 10-20% of patients with NSCLC in the US, while the incidence can be as high as 50% in Asia.

Three EGFR TKIs approved as first-line therapy in the United States are available: erlotinib, afatinib, and gefitinib.

Erlotinib and gefitinib are considered first-generation TKIs.

They have higher binding affinity for the 2 common EGFR mutations than wild-type EGFR.

In addition, they reversibly bind to the intracellular tyrosine kinase domain, resulting in inhibition of autophosphorylation of the tyrosine residues.

Afatinib, a second-generation and irreversible TKI, targets EGFR (HER1) as well as HER2 and HER4.

A third line TKI osermertinib can also target the EGFR T790 resistance mutation and avoid targeting wild type EGFR which reduces its off target toxicity such as rash.

Osimertinib reduces the risk of disease progression by 54% over gefitinib  and erlotonib  and reduces mortality by 20%: median progression free survival of 18.9 months and median overall survival of 38.6 months with the single agent therapy.

First line treatment with osimertinib plus chemotherapy led to significantly longer progression free survival than osimertinib  monotherapy among patients with EGFR mutated advanced NSCLC (FLAURA2 investigators).

The superior efficacy of the EGFR TKIs over platinum doublet chemotherapy in treatment-naive patients with EGFR mutations has been demonstrated in multiple randomized trials.

Despite a remarkably high overall response rate of approximately 60-75% to TKIs all patients with the EGFTmutations will develop secondary resistance within average median progression free survival ranging from 9 to 15 months.
None of the first line TKIs have proved an overall survival benefit in EGFR  mutated non-small cell lung cancers.

Patients with exon 19 deletions, nonsmokers, and women had even better outcomes.

The important toxicities associated with EGFR TKIs are rash, gastrointestinal toxicity, hepatic toxicity, and pulmonary toxicity.

Rash is a specific adverse reaction to all agents blocking the EGFR pathway, including small molecules and monoclonal antibodies such as cetuximab.

The epidermis has a high level of expression of EGFR, which contributes to this toxicity.

Rash usually presents as dry skin or acneiform eruption.

Diarrhea is the most prevalent gastrointestinal toxicity.

Hepatic toxicity is often manifested as elevated transaminases or bilirubin.

Interstitial lung disease is rare.

The median PFS of patients with EGFR mutations treated with any 1 of the 3 TKIs is around 9 to 13 months.

The T790M mutation is found in approximately 60% of patients who progress after treatment with first-line TKIs.

Other mechanisms of TKI resistance such as HER2 amplification, MET amplification, or rarely small cell transformation, have been reported.

TKIs, first- and second-generation EGFR TKIs, function by binding to the ATP-binding domain of mutated EGFR, leading to inhibition of the downstream signaling pathways and ultimately cell death.

The T790M mutation hinders the interaction between the ATP-binding domain of EGFR kinase and TKIs, resulting in treatment resistance and disease progression.

Osimertinib is a third-generation irreversible EGFR TKI with activity against both sensitizing EGFR and resistant T790M mutations.

Osimertinib (Tagrisso) has low affinity for wild-type EGFR as well as insulin receptor and insulin-like growth factor receptor.

Osimertinib approved for NSCLC patients with EGFR mutations who have progressed on first-line EGFR TKIs with the development of T790M mutation.

Osimertinib is the preferred agent for patients with an exon 19 deltion or an L858R mutation, in exon 21 of the EGFR gene..

Osimertinib adjuvant therapy is recommended for patients with non-small cell lung cancer of 3 cm or greater size lesions or positive lymph nodes with EGFR sensitizing mutations for three years after completion of appropriate stage chemotherapy.
Afatinib is he approved agent for G719X mutation.
Patients with EGFR exon 20 insertions have two approved agents: bispecific anybody amivantamab  and the oral tyrosine kinase inhibitor mobocertinib.msdfgffgg

ALK rearrangements are found in approximately 2% to 7% of NSCLC, with EML4-ALK being the most prevalent fusion variant.

The inversion of chromosome 2p leads to the fusion of the EML4 gene and the ALK gene, which causes the constitutive activation of the fusion protein and ultimately increased transformation and tumorigenicity.

ALK rearrangements tend to occur in non-smokers.

Adenocarcinoma, especially signet ring cell subtype, is the predominant histology.

Compared to EGFR mutations, patients with ALK mutations are significantly younger and more likely to be men.

ALK rearrangements can be detected by either FISH or IHC,.

Crizotinib is the first approved ALK inhibitor for the treatment of NSCLC with molecular subset of patients.

PROFILE 1014 is a phase 3 randomized trial that compared crizotinib with chemotherapy containing platinum/pemetrexed for up to 6 cycles.

The crizotinib arm demonstrated superior PFS (10.9 months versus 7 months) and overall response rates of 74% versus 45%.

Crizotinib is considered standard of care in the United States for treatment-naïve patients with advanced NSCLC harboring ALK rearrangements.

The current recommended dose is 250 mg orally twice daily.

Common treatment-related adverse reactions of all grades include vision disorder (62%), nausea (53%), diarrhea (43%), vomiting (40%), edema (28%), and constipation (27%).

PROFILE 1007 compared crizotinib with pemetrexed or docetaxel in ALK-rearranged NSCLC patients with prior exposure to 1 platinum-based chemotherapy: The median Progression free survival was 7.7 months for crizotinib as compared to 3 months for chemotherapy.

In the PROFILE 1007 trial the response rates were 65% and 20% for crizotinib and chemotherapy, respectively.

Ceritinib is an oral second-generation ALK inhibitor that is 20 X more potent than crizotinib, that is based on enzymatic assays.

Ceritinib also targets ROS1 and insulin-like growth factor1.

Ceritinib does not target c-MET receptor.

It has been approved for treatment-naI’ve patients.

ASCEND-4 trial, a randomized phase 3 trial assessing the efficacy and safety of ceritinib over chemotherapy in the first-line setting: The median progression free survival was 16.6 months for ceritinib versus 8.1 months for chemotherapy.

Toxicities of ceritinib are gastrointestinal: diarrhea, nausea, vomiting, abdominal pain, and constipation of all grades were seen in 86%, 80%, 60%, 54%, and 29% of patients, respectively.

Other common side effects include: fatigue and decreased appetite, anemia, increased liver functions, azotemia, hyperglycemia, hypophosphotemia, and increased lipase.

Due to adverse events the incidence of dose reduction was about 58% and the median onset was around 7 weeks.

Alectinib is another oral second-generation ALK inhibitor approved for the treatment of NSCLC patients with ALK rearrangements who have progressed on or are intolerant to crizotinib.

Alectinib is a potent and highly selective TKI of ALK73 with activity against known resistant mutations to crizotinib.

Alectinib also inhibits RET but not ROS1 or c-MET.

In the ALEX trial, a randomized phase 3 study, compared alectinib with crizotinib in treatment-naI’ve patients with NSCLC harboring ALK rearrangements: The 12-month event-free survival was 68.4% versus for alectinib and crizotinib, respectively.

Brigatinib, another oral second-generation ALK inhibitor for ALK-rearranged and crizotinib-resistant NSCLC based on the ALTA trial.

This randomized phase 2 study of brigatinib showed an ORR of 54% (97.5% CI 43% to 65%) in the 180 mg once daily arm with lead-in of 90 mg once daily for 7 days.

Median PFS was 12.9 months.

The F1174V mutation has been reported to confer resistance to ceritinib but sensitivity to alectinib, while the opposite is true for I1171T.

The G1202R mutation is resistant to ceritinib, alectinib, and brigatinib, but lorlatinib, a third-generation ALK inhibitor, has shown activity against this mutation.

All of the second and third generation ALK inhibitors have demonstrated better central nervous system activity than crizotinib.

Approximately 2.4% of lung adenocarcinomas harbor ROS1 rearrangements.

ROS1 genetic alteration occurs more frequently in NSCLC patients who are younger, female, and never-smokers, and who have adenocarcinomas.

ROS1 rearrangements rarely overlap with other genetic alterations including KRAS mutations, EGFR mutations, and ALK rearrangements.

ROS1 as a receptor tyrosine kinase, is similar to ALK and insulin receptor family members.

Crizotinib, which targets ALK, ROS1, and c-MET is approved for the treatment of metastatic ROS1-rearranged NSCLC.

Studies revealed Crizinotib in ROS1 positive NSCLC patients has an overall response rate of 72%, a median duration of response of 17.6 months.

BRAF mutations play an important role in the mitogen-activated protein kinase (MAPK) signaling pathway.

BRAF mutations have been increasingly recognized also as driver mutations in NSCLC.

The incidence is about 2.2% among patients with advanced lung adenocarcinoma and 50% of mutations are V600E, while G469A and D594G accounted for the remaining 39% and 11% of patients, respectively.

All patients were either current or former smokers.

For patients with BRAF V600E-mutant NSCLC who have progressed on platinum based chemotherapy, the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) may be beneficial.

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