Current Drug Pathways in Non–Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is a collection of different entities with 3 major subtypes (Figure 1¹). Advancements in genomic and mutational analysis show that up to 60% of adenocarcinomas and up to 50% to 80% of squamous cell carcinomas (SCC) have a known oncogenic driver mutation (Figure 2,^1-3 Figure 3¹). These driver mutations ultimately lead to uncontrolled growth, proliferation, and survival; they also serve as potential targets for therapeutics.¹

Adenocarcinoma by far has seen the most progress, with targeted agents proving useful against the various driver mutations that can be found in the histology of these cancers.^1,2 Additionally, immune checkpoint inhibitors have proven useful for the treatment of SCLC and NSCLC.^2,3

Historical Perspective on NSCLC Treatment

In NSCLC, the historical treatments have been platinum-based doublets. The typical 5-year survival for patients with metastatic NSCLC receiving only chemotherapy is approximately 6%, based on extended analysis of the KEYNOTE-001 (NCT01295827) phase 1 study, whereas the 5-year survival rate for those eligible for immunotherapies or targeted therapy ranges from 15% to 50%, depending on the biomarker.2,4 Furthermore, it is important to know that the initial response rates, median progression-free survival (PFS), and median overall survival (OS) that are associated with first-line platinum doublet therapies are around 15% to 32%, 3 to 5 months, and 9 to 12 months, respectively.^5-9

In the second-line or subsequent-line setting, pemetrexed (Alimta; Eli Lilly & Company) and docetaxel (Taxotere; Sanofi) generated overall response rates (ORRs) of 9.1% and 8.8%, respectively, in clinical trials. Median PFS was 2.9 months for each drug, whereas median OS was around 8 months for both.¹⁰

Therapeutic Pathways With Drugs in NSCLC

Sensitizing EGFR Mutations

EGFR mutations are most common in nonsmokers or former light smokers with adenocarcinoma histology. The 2 most common EGFR gene mutations are deletions in exon 19 in 45% of patients and a point mutation in exon 21 (L858R) in 40%. Current drugs in use include osimertinib (Tagrisso; AstraZeneca), which is the current standard of care for first-line treatment; dacomitinib (Vizimpro; Pfizer); afatinib (Gilotrif; Boehringer Ingelheim); erlotinib (Tarceva; Genentech); and gefitinib (Iressa; AstraZeneca).^2,11

Additionally, use of osimertinib has recently moved to the adjuvant setting for stage IB-IIIA NSCLCs that have a sensitizing EGFR mutation.^2,12 Tumors with EGFR mutations do not respond to immune checkpoint inhibitors (ICIs) except for the atezolizumab (Tecentriq; Genentech) quadruplet regimen.²

EGFR Exon 20 Insertion Mutations

EGFR exon 20 insertion mutations account for 4% to 10% of EGFR mutations seen. Until now, patients with EGFR exon 20 mutations have had poor outcomes when treated with available EGFR tyrosine kinase inhibitors (TKIs). Amivantamab is a bispecific antibody directed against MET receptors and EGFR and was studied in those who progressed on or following platinum-based chemotherapy. In the phase 1 CHRYSALIS study (NCT02609776), amivantamab elicited an ORR of 40% (3.7% were complete responses and 36.3% were partial responses). Immature data for median OS and PFS have been shown to be 22.8 months and 8.3 months, respectively.

ALK Rearrangements

ALK fusions are the result of a rearrangement of the ALK gene, which codes for a tyrosine kinase, and another gene product—most commonly EML4. Their resulting fusion product is a constitutively active kinase that increases cellular proliferation and survival.²

Tumors with ALK mutations do not respond to ICIs.2 Current drugs include alectinib (Alecensa; Genentech), the standard of care for first-line treatment; brigatinib (Alunbrig: Takeda Oncology); ceritinib (Zykadia; Novartis); crizotinib (Xalkori; Pfizer); and lorlatinib (Lorbrena; Pfizer).

ROS1 Rearrangements

The ROS1 tyrosine kinase is very similar to ALK in molecular function. ROS1 tends to occur more frequently in those who are negative for EGFR mutations, KRAS mutations, and ALK gene fusions. Response to ICIs is truncated with ORRs at 17%.² Current drugs include crizotinib, a preferred first-line treatment; ceritinib; entrectinib (Rozlytrek; Genentech), a preferred first-line treatment; and lorlatinib, which is reserved for second-line treatment.²

BRAF V600E Mutations

BRAF is a serine/threonine kinase that is part of the MAP/ERK kinase pathway. Mutations of the BRAF gene are associated with more aggressive tumor histology and a poorer prognosis. Patients with BRAF mutations respond to ICIs at a rate of 24%.² Current targeted agents for these mutations include dabrafenib (Tafinlar; Novartis) plus trametinib (Mekinist; Novartis), which is preferred; or vemurafenib (Zelboraf; Genentech) monotherapy.²

NTRK1/2/3 Gene Fusions

NTRK genes encode for 3 TRK proteins (TRKA, TRKB, and TRKC) that play an important role in cellular growth, differentiation, and apoptosis of peripheral and central nervous system neurons. NTRK fusions occur
in NSCLC at a rate between 0.2% and 4%.^2,13,14 It is unknown whether there are ethnic-related or social behavior-related predilections for NTRK mutations.¹⁵ Current therapies include larotrectinib (Vitrakvi; Bayer) and entrectinib.

MET exon 14 (METex14) Skipping Mutations

METex14 skipping mutations are found in approximately 3% of NSCLC cases and are found more often in females, patients 70 years or older, nonsmokers, and in patients with pulmonary sarcomatoid carcinoma. METex14 skipping mutations are associated with poor prognosis and, unlike KRAS and BRAF mutations, response to immunotherapy is truncated to ORRs of 16% to 17%.^2,3,16 Current guideline-recommended agents include capmatinib (Tabrecta; Novartis), tepotinib (Tepmetko; EMD Serono), and crizotinib. Additionally, the investigational drug savolitinib (AZD6094; AstraZeneca) is a selective MET inhibitor that is being studied.²

RET Rearrangements

RET rearrangements occur when the gene that codes for RET fuses with other genes, leading to a fusion RET protein that is overexpressed and increases cellular proliferation. RET fusions are oncogenic drivers in 1% to 2% of NSCLC diagnoses.

Immunotherapy response is minimal with responses of 6%. The current agents that can be used include selpercatinib (Retevmo; Eli Lilly and Company), a preferred treatment; pralsetinib (Gavreto; Blueprint Medicines and Genentech), a preferred treatment; and cabozantinib and vandetanib (Caprelsa; Sanofi Genzyme).^2,3,17-20

PD-1/PD-L1 Axis

ICIs that target PD-1/PD-L1 axis work by reversing tumor-mediated inactivation of T cells and improving immune antitumor response. Classwise, PD-1 receptor inhibitors include nivolumab (Opdivo;Bristol Myers Squibb), pembrolizumab (Keytruda; Merck), and more recently cemiplimab (Libtayo; Regeneron Pharmaceuticals and Sanofi Genzyme), whereas atezolizumab and durvalumab (Imfinzi; AstraZeneca) inhibit PD-L1.^2,21

ICIs are typically used in patients negative for driver mutations and have essentially eliminated the need to use chemotherapy by itself in the first-line setting, except in cases where contraindications to immunotherapy exist. At present, all first-line regimens for NSCLC in this setting include ICIs. Additionally, when PD-L1 expression is 50% or more, pembrolizumab, atezolizumab, or cemiplimab can be used as monotherapy.^2,21-23

HER2 Mutations

HER2 (or ERBB2) differs from EGFR (ERBB1) in that it does not have an endogenous ligand. It promotes oncogenesis through heterodimerization with other members of the ERBB family that then activate various kinase pathways (Figure 4¹). Despite a rough start with other anti-HER2 agents, TDM-1 or ado-trastuzumab emtansine and trastuzumab deruxtecan have shown much higher ORRs.^24-27

KRAS

KRAS is a G protein with GTPase activity and is a part of the MAP/ERK pathway; point mutations in the KRAS gene commonly occur at codon 12.² KRAS mutations confer shorter survival and predict nonresponsiveness to EGFR TKIs. Additionally, KRAS mutations do not appear to affect chemotherapeutic efficacy and, contrary to many of the other driver mutations, they seem to respond to immunotherapy.²

Despite years of research on the subject, attempts at inhibiting KRAS met with failure. However, more recently, hope has been restored due to presented data from a phase 2 trial (NCT03600883) of sotorasib (Lumakras; Amgen), a TKI that inhibits the KRAS G12C mutation by binding to KRAS in its inactive GDP state. The KRAS G12C mutation occurs in approximately 13% of patients with NSCLC, and therefore accounts for roughly half of all KRAS mutations.²⁸

Hot on the heels of sotorasib is adagrasib (MRTX849), another KRAS G12C kinase inhibitor. It differs from sotorasib in that it exhibits a much longer half-life of 24 hours compared with 5 hours for sotorasib, which is important because KRAS G12C is regenerated every 24 to 48 hours.^29-31

Conclusion

Lung cancer therapeutics are numerous and varied and depend on the histologic subtype that is being treated. The molecular pathways of SCLC and SCC NSCLC are still being researched, whereas adenocarcinoma by far has had the most innovation with the discovery of different driver mutations that support oncogenesis but also serve as a therapeutic target. There is still more research to be completed, but advancement seems probable, even if made only 1 step at a time.

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