Precision and Immune-Based Therapies

Targeted Therapies

Targeted therapy is the use of agents (typically small molecules, but sometimes monoclonal antibodies, or mAbs) to target cancer cells based on unique biomarkers (typically mutations or other alterations in key proteins) present only in the tumor, thus sparing normal tissues. Targeted therapy has revolutionized the treatment of non-small cell lung cancer (NSCLC); if a driver oncogene can be identified, targeted therapy is the standard of treatment for Stage IV disease. For resectable tumors (Stage I to IIIA) with a targetable mutation, targeted therapy is the standard of care for adjuvant therapy following surgical resection. Targeted therapy is an active field of research, including novel drug discovery (see the Emerging Therapies and Research sub-section below) and broadening the use of existing agents (e.g., results from the LAURA trial show that targeted therapy used in the adjuvant setting after chemotherapy may extend PFS in patients with non-resectable stage III disease). There are now many Food and Drug Administration (FDA)-approved drugs that target mutations (including rearrangements) in genes including Epidermal Growth Factor Receptor (EGFR),  anaplastic lymphoma kinas (ALK), Kirsten Rat Sarcoma Viral Oncogene (KRAS), Proto-Oncogene Tyrosine-Protein Kinase (ROS1), B-Raf Proto-Oncogene (BRAF), Mesenchymal-Epithelial Transition Factor (MET), Rearranged during Transfection (RET), Neurotrophic Tyrosine Receptor Kinase (NTRK), and human epidermal growth factor receptor (HER2). An overview of available targeted therapies and their targets is shown in Figure 3-4.

Epidermal growth factor receptor (EGFR) is a transmembrane receptor which, upon binding of a ligand, auto-phosphorylates and triggers an intracellular signaling cascade. The signaling promotes cell proliferation, invasiveness, metastasis and neoangiogenesis, while inhibiting apoptosis. Among patients with adenocarcinoma, mutations in EGFR are found in ~15% of patients in the West and up to 50% of patients in Asia. The two most common mutations, accounting for 85-90% of NSCLC with EGFR mutations, include an in-frame deletion of <10 amino acids in exon 19 and the L858R missense mutation in exon 21. First generation EGFR-targeting tyrosine kinase inhibitor (TKIs), including gefitinib and erlotinib, showed good efficacy in prolonging Progression-Free Survival (PFS) of patients with metastatic NSCLC who had the common mutations. Second-generation drug (afatinib, dacomitinib) bind irreversibly to EGFR and have demonstrated better PFS and overall survival (OS) than first-generation TKIs. However, resistance emerged soon after the first-generation TKIs came into use. The most common resistance mutation (arising in up to 60% of patients treated with anti-EGFR TKIs) is T790M, which sterically blocks first- and second-generation TKIs from inhibiting EGFR signaling. The third-generation anti-EGFR TKI osimertinib can overcome the resistance conferred by T790M, and is currently the TKI of choice for the treatment of EGFR-mutated NSCLC. Certain mutations, such as EGFR exon 20 insertions, are resistant to all three generations of EGFR TKIs. Amivantamab, a bispecific mAb which targets both EGFR and MET, was initially approved by the FDA in 2021 for the treatment of locally advanced or metastatic NSCLC with EGFR exon 20 insertions that progressed on or after platinum chemotherapy. In 2024, lazertinib, a third-generation TKI with activity against EGFR exon 19 deletions and the exon 21 L858R substitution, received FDA approval for use in combination with amivantamab for the first-line treatment of locally advanced or metastatic NSCLC with EGFR exon 19 deletions or the L858R substitution. In 2024, amivantamab also received FDA approval in combination with carboplatin and pemetrexed chemotherapy for the first-line treatment of locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations and for the treatment of locally advanced or metastatic NSCLC with EGFR exon 19 deletions or the L858R substitution that progressed on or after an EGFR TKI.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase with physiological roles in the nervous system, particularly during development. An estimated 5-7% of patients with adenocarcinoma have tumors with rearrangements involving a chromosome 2p inversion which fuses ALK with another gene (most commonly echinoderm microtubule–associated protein-like 4, or EML4). This produces a fusion protein that lacks the regulatory domain of ALK, leading to constitutive activation of the kinase, which in turn activates Ras/Mek/Erk and PI3K/Akt signaling, promoting cell proliferation and survival. The first ALK-targeted TKI, crizotinib, was originally developed as a MET inhibitor, but was found to also inhibit ALK by reversibly binding to its ATP-binding site. However, it has poor penetration into the central nervous system (CNS) and is thus less efficacious against brain metastases, which are common in ALK alteration-positive NSCLC. Crizotinib is also susceptible to many resistance mutations, including the L1196M “gatekeeper mutation”. Second-generation ALK TKIs, including alectinib and brigatinib, bind ALK irreversibly, show better penetration into the brain and can overcome many of the resistance mutations that inhibit crizotinib. They also significantly improve PFS compared to crizotinib. However, resistance against second-generation agents also quickly evolved to sterically inhibit the binding of second-generation TKIs to ALK; the G1202R mutation is a common variant with resistance against second-generation TKIs. The newest anti-ALK TKI to receive FDA approval, lorlatinib, is considered a third-generation agent. It has broad activity against a wide range of resistance mutations, including G1202R and excellent CNS activity. In one trial, 82% of lorlatinib-treated patients exhibiting an intracranial response, and 71% showed a complete intracranial response (i.e., disappearance of all target brain lesions).

Kirsten Rat sarcoma virus protein (KRAS) is a small GTPase which activates several downstream signaling pathways, including Ras/Mek/Erk and PI3K/Akt, which control cell proliferation and survival. The signaling pathways are activated only while KRAS is bound to GTP; KRAS becomes inactivated when its inherent GTPase function converts the GTP do GDP. Mutations in KRAS are the most common oncogenic mutations in NSCLC in Western populations; they are found in up to 30% of NSCLC tumors. They are also more common in smokers than non-smokers. The most common specific KRAS mutations are G12C (found in ~40% of all tumors with KRAS mutations), G12V (21%) and G12D (17%). These mutations impair the GTPase function of the KRAS protein, locking it in its active form. The FDA has recently approved two KRAS inhibitors for the G12C mutation: sotorasib and adagrasib. These molecules bind the mutant cysteine residue in G12C, which forces the protein into the inactive conformation. Sotorasib and adagrasib showed a good objective response rate in Phase 2 trials and received accelerated FDA approval based on those results.

Other NSCLC-associated genomic alterations are found less often but are nevertheless critically important to the success of the tumors in which they occur. Mutations in MET are found in ~4% of adenocarcinomas, BRAF in 3-4%, HER2 in 2-4%, NTRK1-3 in 2-3%, RET in 1-2% and ROS1 in 1-2%.

The MET gene encodes the RTK for hepatocyte growth factor/scatter factor. The specific oncogenic MET mutations which can be targeted are exon 14 skipping mutations. Two drugs – capmatinib and tepotinib – are specific to MET, but crizotinib can also target MET (in addition to ALK).

BRAF is a nonreceptor serine/threonine kinase that activates MAP signaling; the most common oncogenic mutation in BRAF is V600E (accounting for ~50% of BRAF mutations). A combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib is FDA approved for the treatment of NSCLC with the V600E mutation in BRAF.

Alterations in the RTK-encoding gene HER2 (also known as ERBB2) include gene mutation (1%-4% of cases), gene amplification (2%-5%) and protein overexpression (2%-30%). The only currently approved targeted therapy for HER2 mutated cancer is trastuzumab deruxtecan; unlike the other targeted drugs discussed so far, trastuzumab deruxtecan is not a small molecule but an antibody-drug conjugate. It combines an antibody against the mutant HER2 receptor (trastuzumab) with a cytotoxic drug (deruxtecan), allowing precise targeting of the drug to the cancer cells.

The neurotrophin kinase (NTRK) genes NTRK1-3 code for tropomyosin-related tyrosine kinases whose physiological role is not yet fully elucidated. Genomic rearrangements involving the NTRK genes can produce constitutively active fusion proteins which promote oncogenic RAS/RAF/MEK signaling. Two small molecule inhibitors of NTRK signaling have received FDA approval to date: larotrectinib, which is NTRK-specific and entrectinib, which also inhibits ROS1 and ALK. These drugs are approved tumor-agnostic indications, ie, they are approved for any cancer that harbors an NTRK gene fusion (including NSCLC).

The RET gene codes for an RTK whose normal expression pattern is confined to tissues derived from the neural crest. At least 12 RET rearrangements have been described to date in NSCLC; KIF5B-RET is the best understood. Like many other similar fusions, the KIF5B-RET protein is capable of ligand-independent autophosphorylation and pro-oncogenic downstream signaling. Two highly specific RET fusion inhibitors have been approved by the FDA thus far: selpercatinib and pralsetinib. These drugs are indicated as a first-line option in RET-mutated NSCLC.

The last NSCLC-related oncogene that we will survey is ROS1. It encodes an RTK whose physiologic role is not yet known. Several rearrangements have been identified which result in a constitutively active ROS1 kinase; the CD74-ROS1 fusion is believed to the most common ROS1 alternation in NSCLC. Since ROS1 is structurally related to ALK, ROS1 fusion proteins can be targeted by agents that also inhibit ALK; crizotinib and entrectinib have been used in this context.

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Immunotherapy

Immunotherapy, broadly defined, is a form of cancer treatment that acts through or potentiates the immune system to recognize and destroy cancer cells. The most widely used form of immunotherapy at present are immune checkpoint blockers/inhibitors (ICBs) and this is the only immunotherapy approved for NSCLC, but other immune-based therapies are actively being tested.

Immune checkpoint blockers are inhibitors of pathways that suppress the immune response, allowing T cells to more effectively target and destroy cancer cells. Many such suppressive pathways exist (Figure 3-5) but only two have to date been targeted by immunotherapy: the PD-1/PD-L1 pathway and the CTLA-4 pathway. The PD-1 (programmed death-1) receptor is expressed on the surface of activated T cells. When this receptor interacts with PD-L1 (programmed death ligand-1) on the surface of another cell, the activation of the T cell is attenuated. Many cancer cells express PD-L1, allowing them to impair T cell function and evade destruction. Tumors with high PD-L1 expression are observed in 24-60% of patients with NSCLC. The CTLA-4 pathway operates between T cells and antigen presenting cells (APCs). The T-cell surface receptor CTLA-4 competes with CD28, another T-cell receptor, for binding to the CD80/CD86 ligand on APCs. While the CD28-CD80/CD86 interaction is immunostimulatory, the CTLA-4-CD80/CD86 is immunosuppressive.

Thus, the PD-1/PD-L1 and the CTLA-4 pathways are immune checkpoints which create an immunosuppressive environment within the tumor. The potential to exploit this therapeutically led to the development of ICBs: thus far, all ICBs have been mAbs that bind to a receptor or ligand and prevent the activation of the immunosuppressive checkpoint. In order of approval for the treatment of NSCLC, ICBs include: nivolumab, pembrolizumab, atezolizumab, durvalumab, ipilimumab, cemiplimab, and tremelimumab (Table 3-1). The field of NSCLC therapeutics is constantly evolving; please consult the current FDA documentation for the most up-to-date information on approved agents and their uses.

Immunotherapy has changed the standard of care for NSCLC, offering significant improvements in both OS and PFS compared to traditional chemotherapy. However, unlike targeted therapies which are primarily used on their own, ICBs are commonly used in combination with other therapies – whether chemotherapy, other immunotherapy, or radiotherapy. This approach is especially useful in Stage IV disease. Compared to chemotherapy alone, superior OS and PFS have been reported for pembrolizumab with chemotherapy (the KEYNOTE-189 trial), atezolizumab in combination with the angiogenesis inhibitor bevacizumab and chemotherapy (the IMpower150 trial), a combination of nivolumab and ipilimumab with chemotherapy (the CheckMate 9LA trial), and durvalumab with chemotherapy (the POSEIDON trial). Beyond this, ICBs are beginning to be investigated and are increasingly employed in earlier stages of NSCLC, as part of neoadjuvant and adjuvant therapy.

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