Chemotherapy: Biologics

Chemotherapy
Written By Sydney Oesch

Episode Notes

Figure 1: Receptor Tyrosine Kinases: tyrosine kinases are part of cell surface receptors that bind to growth factors.  When growth factor binding is facilitated, this allows for over expression of cells/proliferation. Tyrosine kinases are appealing therapeutic targets as they are located on the cell surface. Non-receptor kinases are enzymes that phosphorylate proteins in the inner cell membrane and cytoplasm (non cell surface receptor). Include kinases that phosphorylate tyrosine residues of target proteins (SRC family) and specific kinases for serine/threonine residues (AKT family). Phosphatases (like PTEN) oppose activity of kinases), PTEN is a tumor suppressor which negatively regulates the PI3K signaling pathway.

Image from: https://www.nature.com/articles/s41392-022-01168-8

Figure 2: Pathways and Target Agents: Combining endocrine and targeted therapies to overcome resistance. Resistance to endocrine therapies is common in hormone-driven cancers. Current strategies to overcome this resistance are focused on inhibiting upstream signaling pathways and CDK4/6. Approved therapies, and those currently in clinical development (italicized), are depicted with mechanisms of action that include targeting estrogens, estrogen receptor (ER), growth signaling pathways, and CDK4/6.

Image from: https://www.sciencedirect.com/science/article/pii/S1048891X24014725

  1. Antiangiogenic therapies

    1. Bevacizumab: covered previously, see show notes from episode 15 - PARPi, Bev, and ovarian cytotoxics 

    2. Tyrosine kinase inhibitors: cell surface receptors which bind to growth factors > proliferation of cells

      1. Most are multikinase inhibitors (i.e. not specific to a single receptor)

      2. Pazopanib (multikinase)

        1. No specific FDA approval in gyn cancers (but has NCCN guideline recommendations)

        2. Oral administration (once daily, without food)

        3. Common AE: fatigue, hypertension, diarrhea, elevated liver enzymes, nausea, vomiting, and abdominal pain

        4. Less common severe AE: 

          1. Cardiotoxicity, with QT prolongation and risk of CHF

          2. Hemorrhagic/thrombotic events

          3. Impaired wound healing

          4. GI perforation and fistulas

        5. Other AE: ILD, PRES, hypothyroidism, proteinuria, infection, tumor lysis syndrome

        6. Management/monitoring for AE

          1. Hepatotoxicity: get liver enzymes at baseline, 2 weeks after starting treatment, repeat throughout treatment

          2. Cardiotoxicity: EKG, electrolytes, echo at baseline and during treatment

          3. Hold around time of surgery to avoid complications with hemorrhage, clotting, wound healing, fistula

      3. Lenvatinib (multikinase)

        1. FDA approval: in combination with pembro for the use in pMMR advanced/recurrence endometrial cancer (KEYNOTE-775/Study 309)

        2. Oral administration (daily, swallow capsules whole, typical dose 20mg)

          1. Dose reductions: down to 8mg/dose (seemingly preserves efficacy)

            1. Can consider starting at a dose <20mg to reduce toxicity

        3. AE (with len/pem together, as lenvatinib currently not used alone in gyn cancer)

          1. 89% of patients experience a grade 3+ event

            1. 5.7% rate of fatal adverse events in the treatment arm

            2. >65% required dose reduction/interruption. 33% discontinued the drug. 

          2. Common: hypothyroidism, hypertension, fatigue, diarrhea, and MSK disorders, which all occur in >50% of patients who take this combination. N/V and stomatitis occur in >⅓ of all patients. 

    3. Monoclonal antibodies

      1. Trastuzumab: MAB against HER2/ERBB2 (part of the EGFR tyrosine kinase family)

        1. Dosed IV

        2. Use is based on Fader paper. See uterine part 3 episode to review use in uterine cancer

        3. AE/unique toxicties

          1. Cardiotoxicity

          2. Infusion reactions

        4. Management/monitoring for toxicities

          1. Cardiotoxicity: pretreatment echocardiogram, repeat every 3 months during treatment and at completion of treatment

            1. Risk higher in patients who previously received anthracycline chemo or chest wall radiation

            2. Hold treatment if there is a reduction in LVEF ≥ 16% from baseline, or if the LVEF is below normal limits and has dropped ≥10% from baseline; if treatment is held for at least 4 weeks and LVEF returns to normal, trastuzumab can be restarted.

          2. Infusion reactions: If a patient experiences anaphylaxis, angioedema, interstitial pneumonitis, or ARDS, treatment should be discontinued and if the reaction is severe, that warrants permanent discontinuation.

    4. Antibody-Drug Conjugates (ADCs):

      1. ADCs include a targeted monoclonal antibody (like HER2), which is fused by a linker to a small cytotoxic molecule, which is known as the payload. Dosed via IV.

      2. Trastuzumab-Deruxtecan (brand name Enhertu): HER2-directed ADC

        1. FDA approval: unresectable/metastatic HER2 positive solid tumors (IHC 3+) (tumor site agnostic)

          1. Gastric cancer IHC cutoffs

          2. Based on DESTINY trials

        2. Deruxtecan = payload = topoisomerase inhibitor

        3. Starting dose: 5.4 mg/kg every 3 weeks, dose reductions available

        4. Common AE: GI (nausea, vomiting, diarrhea, constipation, stomatitis, abdominal pain, dyspepsia); cardiotoxicity (LV dysfunction), fatigue, edema MSK pain, dermatologic (alopecia, rash), respiratory symptoms (URI, cough, pneumonitis, ILD, dyspnea, headaches), cytopenias

        5. Management/monitoring for AE

          1. Emesis: prophylactic antiemetics

          2. Pneumonitis: consider a baseline SpO2, PFTs, and high-resolution CT. Consider repeating the high-resolution CT every 12 weeks, and more frequently if respiratory symptoms are present

            1.  Treatment should be interrupted even with grade 1 pneumonitis, and if patients have grade 2 signs or symptoms, treatment should be permanently discontinued and treatment with steroids initiated

          3. LV dysfunction: 

            1. treatment should be interrupted if LVEF gets below 45% and has decreased 10-20% from baseline 

            2. if LV function recovers to within 10% of baseline, treatment can be resumed, but if LVEF gets below 40% or change from baseline is >20%, treatment should be discontinued permanently.

          4. Cytopenias: see drug website for management recommendations

      3. Mirvetuximab soravtansine (aka MIRV, brand name Elahere)

        1. ADC against folate-receptor-alpha, which is a transmembrane glycoprotein encoded by the FOLR1 gene

          1. FRa has limited expression in normal tissues, elevated expression in ovarian, endometrial and other cancers. Fra overexpression is associated with platinum resistance.

        2. Soravtansine = payload = microtubule disrupting agent

        3. FDA approval: restricted to use in patients with recurrent ovarian cancer with Fra expression ≥75% with moderate to strong staining

          1. NCCN guidelines: also recommend use, in combination with bevacizumab, for patients with Fra expression ≥25%.

          2. Based on MIRASOL, FORWARD I, FORWARD II, SORAYA trials

        4. Dosing: IV, starting dose 6mg/kg (adjusted ideal body weight). Dose reductions available

        5. Unique toxicities

          1. Ocular: blurred vision, keratopathy, dry eye. 11% of patients experience a grade 3+ event

            1. Median time to onset: 5.5w. Only 50% of people with this will have complete resolution. 

          2. Pneumonitis

          3. Peripheral neuropathy

          4. Hepatic toxicity 

        6. Managing/monitoring AE

          1. Premedicate: IV corticosteroid, antihistamine, antipyretic, antiemetic

          2. Ocular: prevent with use of lubricating and ophthalmic topical steroid eye drops; eye exam prior to treatment initiation and throughout treatment.

            1. Cannot wear contact lenses during treatment! 

            2. Consult drug prescribing website for specific management instructions

          3. Hepatic: avoid in patients with moderate to severe hepatic impairment

      4. Tisotumab vedotin (brand name Tivdak)

        1. ADC against tissue factor. TF is expressed on the surface of many tumor cell and is useful for tumor related angiogenesis, thrombogenicity, tumor growth, metastasis.

        2. Vedotin = payload = Monomethyl auristatin E (MMAE), a microtubule disruptor

        3. FDA approval: recurrent or metastatic cervical cancer

          1. Based on InnovaTV study series

        4. Dosing IV, starting dose 2mg/kg q3weeks. Dose reductions available.

        5. Common AE: bleeding/hemorrhagic events (epistaxis, vaginal bleednig), GI toxicity (Nausea, diarrhea/constipation, decreased appetite), ocular (conjunctivitis, corneal toxicity, dry eye), peripheral neuropathy, epistaxis, alopecia, fatigue, anemia

          1. Treatment discontinuation occurred in 15% of experimental arm patients in the study

        6. Management/monitoring of toxicities: depends on grade

          1. Ocular: involve an eye specialist. Often treatment can be held and restarted, but refer to prescribing info for details

            1. Prevention: ophthalmic exam before initiating, throughout treatment, avoid contacts, and use eye drops (steroid, vasoconstriction, lubricating all required), cold packs during treatment

          2. Grade 3+ peripheral neuropathy: permanent discontinuation

          3. Any pulmonary/CNS hemorrhagic events or grade 3+ hemorrhagic events in other organs: permanent discontinuation

          4. Grade 3+ pneumonitis: permanent discontinuation

          5. Grade 3+ severe cutaneous reaction: permanent discontinuation

    5. MEK inhibitors

      1. Trametinib: MEK1 and MEK2 inhibitors; inhibit MAPK pathway

        1. Evaluated in GOG 281, LGSOC

        2. Dosed orally (whole tablets, empty stomach, has to be stored in the fridge!)

          1. 2mg daily starting dose. Reductions available

          2. 70% of patients required at least one dose reduction, >⅓ discontinued

        3. Common AE: 

          1. fatigue, skin rash, anemia, GI AE

          2. Hypertension

          3. Retinal toxicity (2% risk of retinal detachment)

          4. Decreased EF (8% of patients)

        4. Management/monitoring of AE

          1. Consider prophylactic clindamycin cream or acne medication to prevent rashes

          2. Cardiac: echo/cardiac eval prior to initiating

      2. NTRK fusion mutation targeting drugs

        1. NTRK fusions occur in ~1% of all cancers

        2. Larotrectinib: tropomysin receptor kinase inhibitor: blocks downstream signaling of the RAS/MAPK and PI3K/AKT pathways

          1. FDA approval: tumor agnostic for tumors with NTRK gene fusion on molecular testing (from NAVIGATE trial)

          2. Dose: orally, 100mg BID

          3. Unique toxiciites: CNS effects (cognitive impairment, dizziness, mood disorders), skeletal fractures, hepatoxocities

          4. Management/monitoring of AE

            1. Hepatoxicity: if patients have moderate/severe hepatic impairment, start at 50% dose

        3. Entrecitnib: TKI, multikinase (NTRK, ROS1, ALK fusion)

          1. FDA approval: disease agnostic FDA approval for patients with NTRK fusion mutations. In lung cancer, it’s also approved for ROS1 mutations (from STARTRK-2 trial)

          2. Dose: orally, 600mg daily

          3. Has better CNS penetration than larotrectinib (may be a better choice for patients with CNS metastases)

          4. Toxicities, severe/unique: CHF, hyperuricemia, CNS effects (see larotrectinib above), skeletal fractures, hepatotoxicity, CYP3A substrate

          5. Management/monitoring of AE

            1. Cardiac: cardiac eval before and during treatment 

            2. Hyperuricemia: monitor uric acid levels

Sydney Oesch
Previous

Vaginal Cancer
Next

Chemotherapy: IO