Targeted Therapies & Drug-RT Interactions - Rad Onc Board Review

Board review focus: This page summarizes high-yield systemic agents that affect radiation oncology decision-making, including CNS penetration, timing with radiotherapy, and clinically important drug-radiation toxicities. It is intended for educational board review and should be cross-checked against current institutional practice, NCCN guidance, and drug labels.

Master RT Decision Table

Clinical Theme Key Agents Radiation Oncology Takeaway
Strong CNS Penetration Osimertinib, alectinib, lorlatinib, entrectinib, tucatinib-based HER2 therapy May allow deferral of brain RT in selected patients with small-volume, asymptomatic CNS disease. Symptomatic, bulky, hemorrhagic, or threatening lesions still require local therapy.
Hold Around RT BRAF inhibitors and MEK inhibitors High-yield board rule: hold around RT because of severe dermatitis, radiation recall, and visceral toxicity concerns. Many protocols hold at least 3 days before and after fractionated RT and at least 1 day before and after SRS; institutional practice may be more conservative.
Avoid or Use Extreme Caution with Pelvic/GI RT Bevacizumab and other VEGF-pathway agents Risk of bleeding, impaired wound healing, fistula, and bowel perforation. Avoid close sequencing with pelvic or abdominal RT when feasible.
Thoracic RT Caution Immune checkpoint inhibitors, EGFR TKIs, T-DXd, gemcitabine Watch for pneumonitis and enhanced lung toxicity. The clinical issue is especially relevant after thoracic chemoradiation or with large lung V20/mean lung dose.
Marrow-Field Caution CDK4/6 inhibitors, PARP inhibitors, chemotherapy Risk of cytopenias increases with large marrow-bearing fields such as pelvis, spine, or extensive bone metastasis RT. Consider holding depending on field size, intent, and baseline counts.
Exam framing: For radiation oncology boards, the key question is usually not "what is the complete systemic regimen?" but rather "does this drug change my RT timing, toxicity risk, or decision to defer local therapy?"

Part I - Non-Small Cell Lung Cancer

EGFR Mutations - Exon 19 Deletion and L858R

Agent Generation / Setting Board Takeaway & CNS Penetration
Osimertinib 3rd generation EGFR TKI; preferred first-line agent for common sensitizing EGFR mutations Excellent CNS penetration. Active against T790M resistance mutation. Often allows deferral of WBRT or SRS for selected patients with small, asymptomatic brain metastases. Also relevant after definitive chemoradiation for unresectable stage III EGFR-mutant NSCLC.
Afatinib 2nd generation irreversible ErbB inhibitor Acceptable historical first-line option and common board-question distractor. More GI and skin toxicity than first-generation EGFR TKIs.
Erlotinib / Gefitinib 1st generation EGFR TKIs Historical first-line agents. Less CNS-active than osimertinib. Rash and diarrhea are common toxicities.
Rad onc anchor: For unresectable stage III NSCLC, durvalumab after concurrent chemoradiation is a major board topic. In EGFR-mutant unresectable stage III disease, osimertinib after chemoradiation is now also a key modern concept.

ALK Rearrangements

Agent Generation / Setting Board Takeaway & CNS Penetration
Alectinib 2nd generation ALK inhibitor; preferred first-line option Excellent CNS penetration. Superior to crizotinib in the upfront setting. May delay or replace early brain RT in selected asymptomatic patients with CNS disease.
Lorlatinib 3rd generation ALK inhibitor; first-line or later-line option depending on context Excellent CNS penetration. Strong intracranial activity. More concern for neurocognitive, mood, lipid, and metabolic toxicities compared with some earlier ALK inhibitors.
Crizotinib 1st generation ALK / ROS1 / MET inhibitor Historical first-line ALK agent. Poor CNS penetration, with brain relapse as a classic failure pattern.

Other Targetable NSCLC Drivers and Immunotherapy

Target Key Agents Board Takeaway
ROS1 Crizotinib, entrectinib Entrectinib has better CNS penetration than crizotinib. Treat conceptually similar to ALK when thinking about CNS-active systemic therapy.
BRAF V600E Dabrafenib + trametinib Same pathway targeted in melanoma. Hold around RT because BRAF/MEK inhibitors can increase radiation toxicity.
KRAS G12C Sotorasib, adagrasib Targeted options for KRAS G12C-mutant NSCLC, generally after prior systemic therapy. Important because KRAS was historically considered "undruggable."
PD-L1 / Immunotherapy Pembrolizumab, cemiplimab, atezolizumab Used first line in metastatic NSCLC when PD-L1 is high and no actionable EGFR/ALK driver is present. Thoracic RT plus immunotherapy increases the importance of pneumonitis monitoring.
Stage III Consolidation Durvalumab Major rad onc board anchor. Consolidation after concurrent chemoradiation for unresectable stage III NSCLC without progression.

Part II - Melanoma and the BRAF/MEK Hold Rule

BRAF / MEK Inhibitors

The BRAF/MEK RT rule: Hold BRAF inhibitors and MEK inhibitors around radiotherapy because concurrent or close sequencing can cause severe dermatitis, radiation recall, and visceral toxicity. Many protocols hold at least 3 days before and after fractionated RT and at least 1 day before and after SRS, although institutional practice may be more conservative.
Target Key Agents RT Timing and Board Takeaway
BRAF V600E/K Vemurafenib, dabrafenib, encorafenib Effective targeted therapy for BRAF-mutant melanoma. Hold around RT because of risk of severe skin and visceral toxicity.
MEK Trametinib, cobimetinib, binimetinib Usually combined with BRAF inhibitors to improve efficacy and reduce paradoxical secondary skin cancers. Use the same RT-hold approach as BRAF inhibitors.
CTLA-4 / PD-1 Immunotherapy Ipilimumab, nivolumab, pembrolizumab Generally compatible with SRS for melanoma brain metastases. Key toxicity concerns include immune-mediated inflammation, radionecrosis risk, and steroid use potentially blunting immunotherapy effect.
Brain metastasis nuance: For melanoma brain metastases, SRS plus immunotherapy is common. BRAF/MEK inhibitors can be highly active but require careful timing around RT.

Part III - Breast Cancer: HER2, CDK4/6, PARP, and ADCs

Target / Pathway Key Agents Board Takeaway & RT Toxicity
HER2 Monoclonal Antibodies Trastuzumab, pertuzumab Cardiac toxicity with reversible LVEF decline. Generally compatible with breast or chest wall RT, but avoid concurrent use with anthracyclines.
HER2 Antibody-Drug Conjugates T-DM1, T-DXd T-DM1 is used for residual HER2-positive disease after neoadjuvant therapy. T-DXd has an important ILD/pneumonitis warning, including fatal cases; use caution with thoracic RT or lung irradiation.
HER2 CNS-Active Therapy Tucatinib + trastuzumab + capecitabine Important for HER2-positive metastatic breast cancer with brain metastases. May influence sequencing of systemic therapy and SRS in selected patients.
CDK4/6 Inhibitors Palbociclib, ribociclib, abemaciclib Standard with endocrine therapy for ER-positive/HER2-negative metastatic breast cancer. Can cause neutropenia, diarrhea, and fatigue. Use caution with large marrow-bearing RT fields.
PARP Inhibitors Olaparib, talazoparib Used for germline BRCA1/2-mutated HER2-negative breast cancer. Potential marrow toxicity and radiosensitization are practical concerns with larger fields.

Part IV - Gastrointestinal, Genitourinary, and Head & Neck Cancers

EGFR vs VEGF Pathways

Agent Type Key Drugs Disease Sites & RT Interactions
EGFR Monoclonal Antibodies Cetuximab, panitumumab Head and neck: RT plus cetuximab improved outcomes compared with RT alone in cisplatin-ineligible contexts, but cetuximab is inferior to cisplatin for many HPV-positive or cisplatin-eligible patients.
Colorectal: EGFR antibodies require RAS wild-type disease.
Toxicity: Acneiform rash, infusion reactions, and enhanced skin/mucosal reaction with RT.
VEGF Monoclonal Antibody Bevacizumab Colorectal, GBM, cervix, and others: Anti-angiogenic therapy.
RT issue: bleeding, impaired wound healing, fistula, and bowel perforation, especially with pelvic or abdominal RT and close surgical sequencing.

Renal Cell Carcinoma and Prostate Cancer

Pathway Key Drugs Board Takeaway
VEGF / Multi-Target TKIs for RCC Sunitinib, pazopanib, cabozantinib, axitinib, lenvatinib Used in metastatic RCC, often with immunotherapy depending on setting. SBRT is commonly used for oligometastatic or oligoprogressive RCC, but coordinate timing with TKIs because of bleeding, wound healing, and mucosal toxicity concerns.
Androgen Receptor Pathway Inhibitors Abiraterone, enzalutamide, apalutamide, darolutamide Used across metastatic castration-sensitive, non-metastatic castration-resistant, metastatic castration-resistant, and selected high-risk disease settings. Abiraterone requires prednisone and monitoring for hypertension, hypokalemia, edema, and liver toxicity. Enzalutamide and apalutamide are more classically associated with seizure-threshold concern.
PARP Inhibitors in Prostate Cancer Olaparib, rucaparib, talazoparib, niraparib combinations Relevant for homologous recombination repair alterations, especially BRCA1/2. For RT, the practical issue is marrow toxicity and potential radiosensitization.

Part V - Critical Drug-RT Interactions

Exam high-yield: Boards often test when to stop or sequence a systemic agent to avoid severe RT toxicity.
Drug / Class RT Interaction / Risk Management
BRAF/MEK Inhibitors Severe dermatitis, radiation recall, and possible visceral toxicity. Hold around RT. Common approach: at least 3 days before/after fractionated RT and at least 1 day before/after SRS, with institutional variation.
Bevacizumab / VEGF Pathway Bleeding, impaired wound healing, fistula, and GI perforation. Avoid concurrent pelvic or abdominal RT when feasible. Use caution around surgery and mucosal targets.
T-DXd ILD and pneumonitis, including severe or fatal cases. Use caution with thoracic RT, lung irradiation, prior pneumonitis, or high lung dose exposure.
Gemcitabine Potent radiosensitizer with risk of severe local toxicity and necrosis at systemic doses. Do not use full systemic doses concurrently with definitive RT. Concurrent regimens require substantially modified dosing.
Methotrexate Neurotoxicity and leukoencephalopathy risk, especially with WBRT. Avoid concurrent WBRT and high-dose methotrexate. In primary CNS lymphoma, WBRT is often deferred or dose-modified to reduce neurotoxicity.
Anthracyclines Cardiomyopathy and radiation recall. Avoid concurrent use with left-sided breast or mediastinal RT. Sequence carefully.
CDK4/6 Inhibitors Neutropenia and possible enhanced GI or marrow toxicity. Often safe with small palliative fields, but consider holding for large pelvis, spine, or marrow-bearing fields.
Immune Checkpoint Inhibitors Pneumonitis, dermatitis, colitis, hepatitis, endocrinopathies; possible increased radionecrosis risk after CNS SRS. Usually compatible with SRS and many RT courses, but monitor carefully after thoracic RT and CNS SRS. Steroid need may affect immunotherapy efficacy.
Practical board shortcut: CNS-active targeted therapy may help defer brain RT; BRAF/MEK inhibitors should be held around RT; bevacizumab is dangerous near bowel, pelvis, surgery, and mucosal injury; T-DXd and immunotherapy make pneumonitis vigilance essential.