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Targeted Cancer Therapies and Immunotherapy

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tyrosine kinase inhibitorscheckpoint inhibitorsCAR-T
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Targeted cancer therapies and immunotherapy represent a paradigm shift in oncology from cytotoxic chemotherapy toward precision medicine approaches that exploit specific molecular vulnerabilities and immune evasion mechanisms. These agents include tyrosine kinase inhibitors (TKIs), monoclonal antibodies (mAbs), checkpoint inhibitors, CAR-T cell therapies, and small molecule inhibitors targeting specific oncogenic mutations or pathways. The clinical significance is profound, as these therapies offer improved efficacy with often reduced toxicity compared to conventional chemotherapy, though they introduce distinct toxicities and require careful patient selection based on tumor molecular profiling. USMLE Step 2 CK expects detailed knowledge of mechanism of action, clinical indications, monitoring parameters, and immune-related adverse events (irAEs). The expanding landscape of precision oncology has fundamentally changed practice patterns, making understanding of molecular matching and immunotherapy principles essential for board preparation and clinical practice.

The foundation of targeted therapies rests on understanding oncogenic transformation through activating mutations and tumor suppressor loss. Cancer cells depend on specific molecular drivers that can be therapeutically exploited, fundamentally differing from the non-selective toxicity of chemotherapy.

Constitutive Kinase Activation and Signal Transduction Dependency

Many cancers arise from gain-of-function mutations in receptor tyrosine kinases (RTKs) or downstream signaling proteins. For example, Philadelphia chromosome-positive chronic myeloid leukemia (CML) produces BCR-ABL1 fusion protein, a constitutively active tyrosine kinase that drives uncontrolled proliferation through continuous phosphorylation of substrates in the RAS/MAPK, PI3K/AKT, and JAK/STAT pathways. Non-small cell lung cancers (NSCLC) frequently harbor EGFR mutations (L858R, exon 19 deletions) in the tyrosine kinase domain, causing ligand-independent activation and enhanced kinase activity. These mutations create a state of "oncogenic addiction," where cancer cells become exquisitely dependent on the mutant kinase for survival. TKIs competitively inhibit ATP binding to the kinase domain, preventing phosphorylation of downstream substrates and triggering apoptosis in cells dependent on that pathway. The specificity depends on kinase selectivity profiles: erlotinib has high specificity for mutant EGFR, while broader-spectrum inhibitors like sunitinib inhibit multiple kinases (PDGFR, KIT, VEGFR, RET), providing coverage across diverse malignancies but with broader toxicity.

Monoclonal Antibody-Mediated Growth Factor Pathway Disruption

Therapeutic mAbs function through multiple mechanisms targeting growth factor pathways. Trastuzumab (anti-HER2) binds to the HER2 extracellular domain on HER2-overexpressing breast cancers, preventing heterodimerization with other HER family members and blocking downstream signaling through PI3K/AKT and MAPK pathways. Additionally, trastuzumab recruits immune cells (antibody-dependent cellular cytotoxicity, ADCC) through Fc receptor engagement, creating dual mechanisms of action. Bevacizumab (anti-VEGF) neutralizes vascular endothelial growth factor, reducing tumor angiogenesis and the formation of new blood vessels essential for tumor growth beyond 1-2 mm. This disrupts nutrient and oxygen supply, inducing tumor dormancy or regression. Cetuximab (anti-EGFR) competitively blocks ligand binding to EGFR on wild-type EGFR tumors, preventing activation of downstream pathways and inducing antibody-dependent cellular cytotoxicity.

Immune Checkpoint Blockade and T Cell Exhaustion Reversal

Tumors evade immune surveillance through upregulation of programmed death ligand 1 (PD-L1) and other checkpoint ligands on tumor cells and infiltrating immune cells. PD-L1/PD-1 interaction is a critical inhibitory signal: when PD-L1 on tumor cells engages PD-1 on exhausted T cells, it triggers recruitment of phosphatase SHP-2 to the T cell receptor signaling complex, dephosphorylating CD3ζ and ZAP-70, thereby suppressing T cell proliferation, cytokine production, and cytotoxic function. Checkpoint inhibitors like nivolumab (anti-PD-1) and pembrolizumab (anti-PD-1) block this interaction, restoring T cell effector function and enabling tumor cell killing. Similarly, ipilimumab (anti-CTLA-4) blocks CTLA-4, which normally provides co-inhibitory signaling on naive and early-stage T cells in lymphoid tissues; by blocking CTLA-4, ipilimumab enhances T cell priming and activation. These mechanisms explain why checkpoint inhibitors require pre-existing anti-tumor T cells (hot tumors with high tumor infiltrating lymphocytes and high PD-L1 expression) for optimal efficacy, and why they can paradoxically cause immune-related adverse events through uncontrolled T cell activation against self-antigens.

ALK and ROS1 Rearrangements: Fusion Protein Addiction

Some cancers harbor chromosomal rearrangements producing fusion proteins with constitutive kinase activity. ALK (anaplastic lymphoma kinase) rearrangements in NSCLC (EML4-ALK, KIF5B-ALK) produce fusion proteins with permanent kinase domain activation regardless of ligand presence. Crizotinib, a dual ALK/ROS1 inhibitor, competitively blocks ATP binding to these kinase domains. Similarly, ROS1 fusions in NSCLC create ROS1 kinase dependency targetable by crizotinib or more selective agents like entrectinib. The dependence on these fusion proteins explains the rapid and often dramatic responses to targeted kinase inhibition.

BRAF and MEK in MAPK Pathway Malignancies

Melanomas frequently harbor BRAF V600E mutations (~50% of melanomas), which increase kinase activity approximately 500-fold compared to wild-type BRAF. This drives constitutive activation of the MAPK cascade (BRAF→MEK→ERK), promoting proliferation and survival. Vemurafenib specifically inhibits mutant BRAF V600E kinase, while dabrafenib has similar specificity. Importantly, BRAF inhibition alone causes paradoxical activation of MAPK signaling in cells with wild-type BRAF (through increased RTK signaling feedback), explaining why BRAF inhibitors must be combined with MEK inhibitors (trametinib, cobimetinib) to achieve maximal and durable responses. This dual blockade of sequential kinases in the same pathway represents a key principle: targeting pathways at multiple nodes prevents compensatory activation and resistance.

mTOR Inhibition in Tuberous Sclerosis and TSC Loss

The mammalian target of rapamycin (mTOR) pathway is hyperactivated in various cancers through loss of tuberous sclerosis complex (TSC) proteins or PTEN loss. Everolimus and temsirolimus are mTOR inhibitors that block mTORC1 (mechanistic target of rapamycin complex 1), suppressing ribosomal protein S6K and 4E-BP1, reducing mRNA translation and protein synthesis. This leads to G1 cell cycle arrest. These agents are particularly effective in renal cell carcinoma with VHL loss (which leads to HIF activation and downstream mTOR pathway activation) and in neuroendocrine tumors.

PD-L1 Expression Predictive Biomarker

Tumors with high PD-L1 expression by immunohistochemistry (IHC) are more likely to respond to checkpoint inhibitors because the PD-L1 pathway is their primary immune evasion mechanism. However, PD-L1 negativity does not exclude checkpoint inhibitor benefit, as other immune evasion mechanisms (CTLA-4, LAG-3, TIM-3, indoleamine 2,3-dioxygenase, myeloid-derived suppressor cells) may be operative. Microsatellite instability (MSI-high) and high tumor mutational burden (TMB) predict checkpoint inhibitor benefit across cancer types because these tumors generate numerous neoantigens that can be recognized by T cells.

The development of targeted cancer therapies is driven by understanding specific molecular drivers of individual cancers. Risk factors differ fundamentally from traditional cancer risk factors; instead, oncogenic mutations define which patients benefit from particular targeted agents.

Specific Oncogenic Mutations as Primary Drivers

  • EGFR mutations in NSCLC: Predominate in Asian patients (~30-40% in East Asia vs 10-15% in Western populations), female nonsmokers, and adenocarcinoma histology. L858R point mutations and exon 19 deletions comprise 85-90% of sensitizing EGFR mutations. These mutations create absolute dependence on EGFR signaling, making patients exquisitely responsive to EGFR-selective TKIs (erlotinib, gefitinib, afatinib).
  • BCR-ABL1 fusion (Philadelphia chromosome) in CML: Arises from t(9;22) translocation present in 95% of CML cases. This represents a pathognomonic driver mutation defining CML diagnosis and creating absolute dependence on BCR-ABL1 kinase activity.
  • ALK rearrangements (EML4-ALK and others) in NSCLC: Present in 3-5% of NSCLC cases, more common in younger patients and those without smoking history. EML4-ALK represents the most frequent ALK fusion (>85% of ALK-positive cases).
  • HER2 amplification/overexpression in breast cancer: HER2 gene amplification (detected by fluorescence in situ hybridization, FISH) or high HER2 protein expression (3+ by IHC) occurs in approximately 15-20% of invasive breast cancers. ERBB2 amplification creates HER2 dependence, making these tumors responsive to trastuzumab and other anti-HER2 agents. HER2-positive disease historically had worse prognosis; trastuzumab dramatically improved outcomes.
  • BRAF V600E in melanoma: Present in approximately 50% of cutaneous melanomas, less frequent in mucosal and uveal melanomas. Represents a strong prognostic marker and essential for patient selection for BRAF-targeted therapy.
  • PD-L1 expression and tumor microenvironment: PD-L1 is expressed on tumor cells and immune infiltrates in tumors that have generated anti-tumor immune responses but evade them. High expression (>50% tumor cell PD-L1 by IHC) predicts checkpoint inhibitor benefit and serves as a companion diagnostic.
  • Microsatellite instability (MSI-high) and mismatch repair deficiency: Defects in mismatch repair genes (MLH1, MSH2, MSH6, PMS2) cause hypermutation and extraordinarily high tumor mutational burden (up to 10-fold higher than MSS tumors). This predicts durable benefit from checkpoint inhibitors across cancer types (FDA approval for pembrolizumab in all MSI-high solid tumors).
  • ROS1 rearrangements in NSCLC: Present in 1-2% of NSCLC, often mutually exclusive with EGFR and ALK alterations. Create ROS1 kinase dependence targetable by crizotinib, entrectinib, or other ROS1 inhibitors.
  • NTRK gene fusions: Rare but important drivers in various cancers (NSCLC, colorectal cancer, thyroid cancer, salivary gland tumors, pediatric tumors). NTRK (neurotrophin receptor tyrosine kinase) fusions create fusion protein kinase dependence targetable by larotrectinib and entrectinib.

The clinical presentation varies dramatically based on cancer type and stage at diagnosis. Understanding that targeted therapies are not used as single-agent primary treatment for metastatic disease without molecular confirmation is critical.

Presentation of Cancers Amenable to Targeted Therapy

  • NSCLC with EGFR mutations: Often presents as advanced/metastatic disease with constitutional symptoms (fatigue, weight loss, anorexia), respiratory symptoms (dyspnea, cough, hemoptysis), or asymptomatic finding on imaging. Bone metastases present with focal pain; brain metastases present with neurologic symptoms (headache, cognitive changes, ataxia, focal deficits). Unlike squamous histology, adenocarcinoma NSCLC commonly presents as peripheral lung lesions, sometimes discovered incidentally. Pleural effusion (causing dyspnea) is common.
  • CML with BCR-ABL1: Chronic phase often asymptomatic and discovered on routine blood work showing elevated WBC. When symptomatic, patients report fatigue, left upper quadrant pain (from massive splenomegaly), or early satiety. Accelerated phase presents with fever, night sweats, constitutional symptoms, and progressive splenomegaly. Blast crisis presents acutely with symptoms of acute leukemia (bleeding, infections, severe anemia symptoms).
  • HER2-positive breast cancer: Presents with palpable breast mass, nipple discharge, skin dimpling, or axillary lymphadenopathy. Metastatic presentation includes bone pain, dyspnea (from pulmonary/pleural involvement), hepatic dysfunction (from liver metastases), or neurologic symptoms (from brain metastases). HER2-positive tumors historically presented at younger ages with more aggressive biology compared to hormone receptor-positive disease.
  • Melanoma with BRAF V600E: Presents as a changing pigmented lesion, bleeding/oozing mole, or asymmetric dark lesion with irregular borders (ABCDE: Asymmetry, Border irregularity, Color variation, Diameter >6mm, Evolution/change). Metastatic disease presents with regional lymphadenopathy (detected on exam or imaging), subcutaneous nodules, or constitutional symptoms from systemic disease.

Physical Examination Findings Relevant to Targeted Therapy

  • Hepatomegaly or splenomegaly: In CML (especially blast crisis) or metastatic disease involving liver/spleen
  • Lymphadenopathy: Regional or distant depending on cancer type and metastatic burden
  • Skin findings: In melanoma patients, examining entire skin surface and all lymph node basins is essential before initiating checkpoint inhibitors (baseline assessment for irAE monitoring)
  • Neurologic findings: Focal deficits or cognitive changes in patients with brain metastases; ataxia, vertigo in cerebellar involvement
  • Respiratory examination: Crackles/reduced air movement in pulmonary involvement; decreased breath sounds with pleural effusion

Diagnosis of malignancy amenable to targeted therapy requires tissue diagnosis with molecular/genetic testing to identify specific driver mutations. Histopathology alone is insufficient; molecular profiling is now standard of care.

Tissue Diagnosis and Molecular Testing

  • Histopathology with immunohistochemistry: Confirms malignancy and histologic type (adenocarcinoma, squamous, small cell, etc.). For HER2-positive breast cancer, initial screening by IHC (0-3+ scale) with 3+ or equivocal (2+) cases confirmed by FISH showing HER2 gene amplification. FISH is the gold standard; HER2/CEP17 ratio ≥2.0 or average HER2 copy number ≥6 signals confirms HER2 amplification.
  • PCR-based mutation detection for EGFR: Detects sensitizing mutations (L858R, exon 19 deletions, exon 20 insertions, G719X) and resistance mutations (T790M). Exquisitely sensitive (detects mutations in <1% of cells). Performed on tumor tissue (formalin-fixed paraffin-embedded) or plasma cell-free DNA (liquid biopsy). COBAS and other FDA-approved assays detect common EGFR mutations.
  • Fluorescence in situ hybridization (FISH) for ALK and ROS1: Gold standard for detecting ALK rearrangements (EML4-ALK, KIF5B-ALK, others) and ROS1 fusions. Shows physical separation of fusion gene signals under microscopy. ALK FISH positive occurs in 3-5% of NSCLC.
  • Next-generation sequencing (NGS) panels: Comprehensive genomic profiling detects EGFR mutations, ALK/ROS1/NTRK fusions, BRAF V600E, MSI status, TMB, and hundreds of other alterations simultaneously from single tissue specimen. Increasingly standard of care for all solid tumors. Examples include Foundation One CDx, MSK

Class-defining on-target toxicities

  • EGFR inhibitors (erlotinib, osimertinib, cetuximab): acneiform papulopustular rash on face/upper trunk and diarrhea, because EGFR is physiologically required by keratinocytes and gut epithelium; rash severity often correlates with response. Cetuximab additionally causes hypomagnesemia because EGFR signaling drives TRPM6-mediated magnesium reabsorption in the distal convoluted tubule; check magnesium periodically and replete as needed. Cetuximab also causes IgE-mediated infusion reactions against galactose-α-1,3-galactose (alpha-gal). Interstitial lung disease/pneumonitis is uncommon but potentially fatal — any new dyspnea warrants holding the drug.
  • Anti-VEGF agents (bevacizumab, sunitinib): hypertension and proteinuria from loss of endothelial nitric oxide and glomerular podocyte support; also arterial thrombosis, hemorrhage, impaired wound healing, and GI perforation. Per FDA labeling and NCCN, hold bevacizumab for roughly 4 weeks before elective surgery and do not resume until the wound has fully healed (typically at least ~4 weeks postoperatively; the exact interval is protocol- and procedure-dependent), and avoid the drug after recent significant hemoptysis. Monitor blood pressure and urine protein each cycle. Sunitinib also causes hypothyroidism and hand-foot skin reaction.
  • Trastuzumab: reversible, non–dose-dependent left ventricular dysfunction from blockade of HER2 signaling in cardiomyocytes (contrast with cumulative, irreversible anthracycline injury). Baseline and serial echocardiography/MUGA are standard; risk rises with concurrent anthracyclines. Contraindicated in pregnancy (oligohydramnios).
  • BRAF inhibitors: paradoxical MAPK activation in RAS-mutant keratinocytes causes cutaneous squamous cell carcinoma and keratoacanthomas — mitigated by adding a MEK inhibitor, which itself causes retinopathy and decreased LVEF.
  • mTOR inhibitors: stomatitis, hyperglycemia, hyperlipidemia, non-infectious pneumonitis.
  • Imatinib: periorbital/peripheral edema, myelosuppression, transaminitis.

Immune-related adverse events and their reversal

  • Checkpoint inhibitors: unchecked T-cell activity against self-antigens produces colitis, hepatitis, pneumonitis, thyroiditis, hypophysitis (classically ipilimumab), adrenal insufficiency, type 1 diabetes/DKA, nephritis, and rare but highly lethal myocarditis. ASCO and NCCN irAE guidelines direct grade-based management: hold the drug and give corticosteroids (prednisone/methylprednisolone) for moderate-to-severe events; steroid-refractory colitis is treated with infliximab, which is avoided in immune hepatitis (mycophenolate instead). Endocrinopathies are usually permanent and managed with hormone replacement rather than steroids alone. Monitor TSH, LFTs, glucose, creatinine, and cortisol.
  • CAR-T: IL-6–driven cytokine release syndrome — treat with tocilizumab (anti–IL-6 receptor) ± steroids; ICANS responds to corticosteroids, since tocilizumab penetrates the CNS poorly. Also expect tumor lysis syndrome, prolonged cytopenias, and B-cell aplasia/hypogammaglobulinemia requiring IVIG. ASTCT consensus criteria grade both syndromes.
  • Rituximab: screen HBsAg and anti-HBc before therapy (AASLD guidance) given risk of hepatitis B reactivation; rare PML from JC virus.

  • Periorbital edema in a CML patient on imatinib is the classic vignette cue; resistance emerging on therapy points to the T315I gatekeeper mutation — ponatinib is the classic answer for T315I (asciminib, an allosteric STAMP inhibitor, is an alternative). Monitor BCR-ABL1 transcripts by quantitative PCR, not the WBC count, to judge response.
  • Trastuzumab cardiotoxicity is reversible and not dose-dependent — the tested contrast with anthracycline cardiomyopathy, which is cumulative and irreversible. The single best next step for a falling ejection fraction is to hold trastuzumab and repeat imaging, not to switch to an anthracycline.
  • Test RAS before anti-EGFR antibodies in colorectal cancer: cetuximab and panitumumab are ineffective in *KRAS/NRAS*-mutant tumors because the mutation lies downstream of the receptor. The common distractor is treating a RAS-mutant tumor "because EGFR is expressed."
  • New dyspnea and cough on a PD-1 inhibitor is pneumonitis until proven otherwise. Get CT, hold the drug, and start corticosteroids per ASCO/NCCN irAE guidance; the trap answers are "infection" or "disease progression" alone.
  • Fatigue, hypotension, and hyponatremia after ipilimumab = hypophysitis with secondary adrenal insufficiency. Check a morning cortisol and ACTH, and if panhypopituitarism is present, replace glucocorticoid before levothyroxine to avoid precipitating adrenal crisis.
  • High fever, hypotension, and hypoxia days after CAR-T infusion is cytokine release syndrome — the answer is tocilizumab (with steroids for severe or neurotoxic disease), while still covering empirically for sepsis. For confusion, aphasia, or seizure (ICANS), corticosteroids are preferred because tocilizumab does not effectively enter the CNS.
  • Hypertension plus proteinuria on bevacizumab is the on-target VEGF signature; myelosuppression is the distractor imported from cytotoxic chemotherapy. Also remember impaired wound healing and GI perforation.
  • BRAF inhibitor monotherapy causes new cutaneous squamous cell carcinomas via paradoxical MAPK activation — the reason vemurafenib or dabrafenib is paired with a MEK inhibitor.
  • Pembrolizumab is approved tissue-agnostically for MSI-high/mismatch repair–deficient solid tumors, the prototypical "biomarker over histology" question. Check HBsAg and anti-HBc before rituximab.

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