Targeted Therapy & Immunotherapy
Pharmacology · Chemotherapy · lean revision notes
Targeted Therapy & Immunotherapy
Modern oncology has shifted from broad cytotoxic chemotherapy toward drugs that hit specific molecular drivers (kinases, receptors, antigens) or unleash the immune system against tumour cells. For NEET PG, the high-yield game is matching drug → target → tumour → signature toxicity → biomarker.
Big-picture classification
Targeted/biological anticancer agents broadly fall into two structural classes — small-molecule inhibitors (oral, end in -nib, cross cell membrane, hit intracellular kinase domains) and monoclonal antibodies (parenteral, end in -mab, act on cell-surface or soluble targets).
| Suffix | Class | Example | Typical target |
|---|---|---|---|
| -nib | Tyrosine kinase inhibitor (small molecule) | Imatinib, gefitinib, erlotinib | Intracellular kinase domain |
| -mab | Monoclonal antibody | Trastuzumab, rituximab, bevacizumab | Surface antigen / ligand |
| -momab | Murine antibody | (older, immunogenic) | — |
| -ximab | Chimeric (mouse-human) | Rituximab, cetuximab | — |
| -zumab | Humanised | Trastuzumab, bevacizumab, pembrolizumab | — |
| -umab | Fully human | Panitumumab, nivolumab, ipilimumab | — |
| -mus / -limus | mTOR inhibitor | Everolimus, temsirolimus | mTOR |
| -ciclib | CDK4/6 inhibitor | Palbociclib, ribociclib | Cell cycle |
High-yield: Decode the antibody name — the letter before -mab tells you the source: o = mouse, xi = chimeric, zu = humanised, u = fully human. Fully human antibodies are least immunogenic.
The "stem" before that letter hints at the target: -tu(m)- = tumour, -ci- = circulatory/vascular (e.g., bevacizumab → VEGF), -li(m)- = immune.
Small-molecule tyrosine kinase inhibitors (TKIs)
Imatinib — the prototype
Imatinib is a competitive inhibitor of the ATP-binding site of several tyrosine kinases. It blocks three kinases that you must memorise:
- BCR-ABL — the fusion protein from the t(9;22) Philadelphia chromosome in chronic myeloid leukaemia (CML).
- c-KIT (CD117) — driver in gastrointestinal stromal tumour (GIST).
- PDGFR (platelet-derived growth factor receptor) — chronic eosinophilic leukaemia/hypereosinophilic syndrome, dermatofibrosarcoma protuberans.
High-yield: Imatinib is the drug of choice for chronic-phase CML and for unresectable/metastatic GIST. GIST is classically c-KIT (CD117) positive on immunohistochemistry.
Mnemonic — imatinib targets "BCP": BCR-ABL, C-KIT, PDGFR.
Resistance to imatinib arises chiefly from point mutations in BCR-ABL (notably the T315I gatekeeper mutation, which resists almost all TKIs except ponatinib). Later-generation BCR-ABL inhibitors: dasatinib, nilotinib, bosutinib, ponatinib.
| TKI | Notable extra target / use | Key toxicity |
|---|---|---|
| Imatinib | BCR-ABL, c-KIT, PDGFR | Fluid retention, periorbital oedema, myelosuppression |
| Dasatinib | Also SRC; overcomes most BCR-ABL mutations except T315I | Pleural effusion |
| Nilotinib | More potent vs BCR-ABL | QT prolongation, hyperglycaemia |
| Ponatinib | Active vs T315I | Arterial thrombosis, pancreatitis |
High-yield: T315I mutation → ponatinib. Dasatinib → think pleural effusion; nilotinib → think QT prolongation.
EGFR inhibitors
Gefitinib, erlotinib, afatinib, osimertinib inhibit EGFR (HER1) tyrosine kinase — used in non-small-cell lung cancer (NSCLC) harbouring activating EGFR mutations (exon 19 deletion, L858R).
- Osimertinib is third-generation, active against the T790M resistance mutation and is now preferred first-line.
- Cetuximab / panitumumab are anti-EGFR antibodies used in metastatic colorectal cancer — but only if KRAS/NRAS wild-type (RAS mutation downstream makes upstream EGFR blockade futile).
High-yield: EGFR-TKIs cause an acneiform (papulopustular) rash and diarrhoea; rash intensity correlates with response. Anti-EGFR antibodies cause hypomagnesaemia.
Anaplastic lymphoma kinase (ALK) rearranged NSCLC → crizotinib, alectinib. BRAF V600E melanoma → vemurafenib/dabrafenib (often combined with MEK inhibitor trametinib).
Monoclonal antibodies against surface antigens
Trastuzumab — anti-HER2
Trastuzumab is a humanised IgG1 monoclonal antibody against HER2/neu (ERBB2), overexpressed in ~20% of breast cancers and some gastric cancers. It is used when HER2 is 3+ on IHC or amplified on FISH.
High-yield: Trastuzumab's signature toxicity is cardiotoxicity → dilated cardiomyopathy / reduced LVEF / congestive heart failure. Unlike anthracyclines, it is dose-independent and usually reversible. Monitor LVEF by echocardiography. Never give concurrently with doxorubicin (additive cardiotoxicity).
Related HER2 agents: pertuzumab (blocks HER2 dimerisation), T-DM1 (trastuzumab emtansine) and trastuzumab deruxtecan — antibody-drug conjugates (ADCs) delivering a cytotoxic payload. Lapatinib / neratinib are oral HER2 + EGFR TKIs.
Rituximab — anti-CD20
Rituximab is a chimeric antibody against CD20, expressed on B lymphocytes (pre-B to mature B cells, not stem cells or plasma cells). Mechanism: ADCC, complement-dependent cytotoxicity, and apoptosis.
Uses: CD20-positive B-cell non-Hodgkin lymphomas (e.g., diffuse large B-cell lymphoma as part of R-CHOP, follicular lymphoma), CLL, plus autoimmune disease (rheumatoid arthritis, ANCA-associated vasculitis, ITP, pemphigus vulgaris).
High-yield: Rituximab can cause infusion reactions / cytokine release and reactivation of hepatitis B — screen HBsAg/anti-HBc before therapy. Risk of progressive multifocal leukoencephalopathy (PML) due to JC virus.
Bevacizumab — anti-VEGF
Bevacizumab binds circulating VEGF-A, preventing it from activating VEGFR → inhibits tumour angiogenesis. Used in metastatic colorectal, NSCLC, renal cell, glioblastoma, and (ophthalmic, off-label) wet age-related macular degeneration.
High-yield: Class effects of anti-angiogenics — hypertension, proteinuria, arterial/venous thromboembolism, bleeding, impaired wound healing, and GI perforation. Stop before major surgery.
Anti-angiogenic TKIs (multikinase, hit VEGFR): sorafenib, sunitinib, pazopanib, axitinib, regorafenib, lenvatinib — used in renal cell carcinoma, hepatocellular carcinoma, etc. Sunitinib/sorafenib → hand-foot syndrome, hypothyroidism.
| Antibody | Target | Flagship indication | Signature toxicity |
|---|---|---|---|
| Trastuzumab | HER2 | HER2+ breast/gastric | Cardiomyopathy (↓LVEF) |
| Rituximab | CD20 | B-cell NHL, CLL | HBV reactivation, PML, infusion reaction |
| Bevacizumab | VEGF-A | mCRC, NSCLC, RCC, glioblastoma | HTN, proteinuria, thrombosis, GI perforation |
| Cetuximab | EGFR | RAS-WT colorectal, H&N | Acneiform rash, hypomagnesaemia |
| Pembrolizumab | PD-1 | Melanoma, NSCLC, MSI-high | Immune-related adverse events |
| Nivolumab | PD-1 | Melanoma, RCC, NSCLC | irAEs |
| Ipilimumab | CTLA-4 | Melanoma | Severe colitis, hypophysitis |
Immune checkpoint inhibitors
Tumours exploit inhibitory "checkpoint" receptors to switch off T cells. Blocking these checkpoints releases the brakes on cytotoxic T lymphocytes.
Two checkpoint axes are tested:
- CTLA-4 (acts early, in lymph node, on T-cell priming) → blocked by ipilimumab.
- PD-1 / PD-L1 (acts later, in tumour microenvironment) → PD-1 blockers: pembrolizumab, nivolumab, cemiplimab; PD-L1 blockers: atezolizumab, durvalumab, avelumab.
Flow of PD-1 signalling and its blockade:
Tumour cell expresses PD-L1 → binds PD-1 on T cell → T-cell exhaustion / anergy (tumour escapes). Pembrolizumab/nivolumab block PD-1 → PD-L1 can no longer engage → T cell reactivated → tumour killing.
High-yield: Checkpoint inhibitors cause immune-related adverse events (irAEs) — colitis, hepatitis, pneumonitis, dermatitis, and endocrinopathies (hypothyroidism, hypophysitis, type 1 diabetes, adrenal insufficiency). CTLA-4 blockade (ipilimumab) → severe colitis and hypophysitis especially. Treat severe irAEs with corticosteroids (and hold the drug).
Biomarkers predicting checkpoint-inhibitor response: high PD-L1 expression, microsatellite instability-high (MSI-H) / mismatch-repair deficiency (dMMR), and high tumour mutational burden (TMB). Pembrolizumab was the first drug approved on a tissue-agnostic basis (any MSI-H/dMMR solid tumour).
CAR-T cell therapy (e.g., tisagenlecleucel, axicabtagene — anti-CD19) is used in relapsed B-ALL and large B-cell lymphoma.
High-yield: Signature CAR-T toxicities — cytokine release syndrome (CRS), treated with the anti-IL-6 receptor antibody tocilizumab, and ICANS (immune effector cell–associated neurotoxicity).
Biomarker-driven patient selection (emerging exam area)
| Tumour | Biomarker to test | Drug it unlocks |
|---|---|---|
| CML | t(9;22) BCR-ABL | Imatinib |
| GIST | c-KIT (CD117)+ | Imatinib |
| Breast | HER2 (IHC 3+ / FISH amplified) | Trastuzumab |
| Breast/ovary | BRCA1/2 mutation | PARP inhibitor (olaparib) |
| NSCLC | EGFR mutation (exon19/L858R) | Gefitinib/osimertinib |
| NSCLC | ALK rearrangement | Crizotinib/alectinib |
| Colorectal | RAS wild-type | Cetuximab/panitumumab |
| Melanoma | BRAF V600E | Vemurafenib + trametinib |
| Any solid tumour | MSI-H / dMMR | Pembrolizumab (tissue-agnostic) |
High-yield: PARP inhibitors (olaparib) exploit synthetic lethality in BRCA-mutated ovarian/breast cancer — the tumour loses both homologous recombination (BRCA) and base-excision repair (PARP) and dies.
Mechanism-linked toxicity recap
- On-target, off-tumour effects explain most signature toxicities: EGFR is in skin → rash; VEGF maintains vasculature → hypertension/bleeding; HER2 in cardiomyocytes → cardiomyopathy.
- Tumour lysis syndrome can follow rituximab in bulky disease (↑K⁺, ↑PO₄, ↑uric acid, ↓Ca²⁺) — prophylax with hydration and rasburicase/allopurinol.
Recently asked / exam angle
- "Drug targeting BCR-ABL, c-KIT and PDGFR" → imatinib (recurring single-best-answer).
- "Monoclonal antibody causing dilated cardiomyopathy" → trastuzumab.
- "Anti-CD20 antibody / R in R-CHOP" → rituximab; "reactivation of which virus?" → Hepatitis B.
- "Mechanism of bevacizumab" → anti-VEGF, inhibits angiogenesis; toxicity → HTN, proteinuria, GI perforation.
- "PD-1 inhibitor" → pembrolizumab/nivolumab; "CTLA-4 inhibitor" → ipilimumab.
- "T315I mutation–resistant CML, drug?" → ponatinib.
- "Cetuximab works only if ___ status" → RAS/KRAS wild-type.
- "Antibody nomenclature" — identify chimeric vs humanised vs fully human from the suffix.
- "Tissue-agnostic FDA approval / MSI-high tumour drug" → pembrolizumab.
- "CAR-T cytokine release syndrome treated with" → tocilizumab.
- Image/IHC: CD117-positive spindle cell tumour of stomach → GIST → imatinib.
Rapid revision
- -nib = TKI (oral, intracellular); -mab = monoclonal antibody (parenteral, surface/ligand).
- Imatinib targets BCR-ABL, c-KIT, PDGFR → CML + GIST. Resistance: T315I → ponatinib.
- Trastuzumab = anti-HER2; toxicity = reversible dilated cardiomyopathy; never with doxorubicin.
- Rituximab = anti-CD20 B-cell NHL/CLL; risks = HBV reactivation, PML, infusion reaction.
- Bevacizumab = anti-VEGF; class toxicity = HTN, proteinuria, thrombosis, GI perforation, poor wound healing.
- Cetuximab/panitumumab = anti-EGFR; work only in RAS wild-type colorectal; cause acneiform rash + hypomagnesaemia.
- Pembrolizumab/nivolumab = anti-PD-1; atezolizumab = anti-PD-L1; ipilimumab = anti-CTLA-4.
- Checkpoint inhibitors → immune-related adverse events (colitis, pneumonitis, endocrinopathy) treated with steroids.
- EGFR-TKIs (gefitinib/osimertinib) for EGFR-mutant NSCLC; osimertinib covers T790M; rash predicts response.
- MSI-H/dMMR or high TMB predict checkpoint-inhibitor benefit; pembrolizumab = first tissue-agnostic approval.
- PARP inhibitor (olaparib) in BRCA-mutant cancer via synthetic lethality.
- CAR-T (anti-CD19) → cytokine release syndrome → tocilizumab; neurotoxicity = ICANS.