Table 2.

Summary of recommendations for management of selected toxicities to selective RET inhibitors

Hypersensitivity	•Withhold the drug and prescribe steroids (e.g., prednisone 1 mg/kg). •Resume after resolution of symptoms at third dose level. •Gradually increase the dose (one dose level per week) until the original dose is restored. •Continue steroids until target dose is achieved and gradually taper if symptoms remain controlled. •Permanently discontinue the drug if hypersensitivity recur.
Cutaneous toxicities	•Prescribe topical steroids (e.g., hydrocortisone 2.5% cream and/or topical clindamycin [1% gel]) for localized grade 1 or 2 toxicity. •Prescribe oral anti-histaminic in cases with associated pruritus. •Prescribe oral doxycycline (100 mg twice daily) or minocycline (100 mg twice daily) in addition to topical therapy for generalized and mildly symptomatic grade 2 rash. •Prescribe systemic steroids in generalized and severe grade ≥ 3 rash. Withhold the drug until the toxicity improves to grade ≤ 1. •Reassess patients after 2 weeks of supportive treatment. •Resume at a first level-reduced dose. Further subsequent reductions may be considered on the basis of tolerability.
Hepatotoxicity	•Regularly monitor ALT and AST every 2 weeks for the first 3 months then monthly afterward. •Withhold the drug in grade ≥ 3 events and monitor weekly until toxicity decreases to grade 1. •Resume at a reduced dose by 1 dose level for pralsetinib and 2 dose levels for selpercatinib. •Gradually increase the dose until the original dose is restored. •Permanently discontinue if grade ≥ 3 hepatotoxicity recurred.
Stomatitis	•Prescribe topical oral care, bland rinses, and topical anesthetics (e.g., 2% viscous lidocaine swish and spit). •Prescribe 2% morphine mouthwash swish and spit for severe pain. •Prescribe systemic analgesia for symptom control as appropriate. •Consider admission to hospital for fluid and diet intake in case of intense pain.
Dry mouth	•Prescribe topical mucosal lubricants or saliva substitutes, sugar-free (acidic non-erosive or non-acidic) chewing gum and acupuncture. •Prescribe oral pilocarpine or cevimeline and consider transcutaneous electrostimulation in severe cases.
Hematologic toxicities	•Obtain full blood counts prior to each treatment cycle and as clinically indicated. •Withhold treatment in patients with grade 3 or 4 toxicity. •Resume only after recovery to grade 2 or less with the possibility of dose reductions or treatment cessation. •Follow guidelines for management of chemotherapy-induced hematological complications. •Use supportive measures including hematopoietic growth factors whenever appropriate.
Hemorrhagic events	•Withhold the drug in grade ≥ 2 toxicities. •Resume only after full recovery to grade 0 or 1. •Use supportive measures including possible blood transfusions as appropriate. •Permanently discontinue in patients with severe or life-threatening hemorrhage.
QT interval prolongation	•Monitor and correct QT interval, electrolytes, and TSH before starting treatment and periodically while on therapy. •Withhold the drug in grade ≥ 3 toxicities. •Resume only after full recovery to grade 0 or 1 at a reduced dose. •Permanently discontinue in cases with grade 4 events.
Hypertension	•Do not start treatment with RET inhibitors in patients with uncontrolled hypertension. •Regularly monitor hypertension preferably for 1 week then monthly afterward. •Add or optimize hypertensive medications as appropriate in patients with treatment-emergent hypertension. •Withhold the drug in patients with persistent grade 3 or 4 toxicities.
Wound healing	•Withhold selpercatinib 7 days and pralsetinib 5 days before any planned surgery. •Resume after a minimum hold of 2 weeks post-surgery.
Pneumonitis	•Withhold the drug in patients with any grade ILD/pneumonitis. •Prescribe prednisone 1–2 mg/kg/day and taper over 4–6 weeks. •Prescribe empiric antibiotics if infection remains in the differential diagnosis after workup. •Resume treatment after full recovery with appropriate dose reductions. •Permanently discontinue in cases with grade 3 or 4 events and if toxicity recurred for four times despite increasing dose reductions. •Prescribe methylprednisolone i.v. 1–2 mg/kg/day for patients with grade 3 or 4 events. Consider adding immunosuppressive agent (e.g., infliximab, mycophenolate mofetil i.v., IVIG, or cyclophosphamide) if no improvement occurred after 48 hours.
Edema and chylous effusions	•Use drainage for immediate symptoms relief in symptomatic effusions. •Include a high-protein and low-fat diet with medium-chain triglycerides, reducing the ingestion of long-chain triglycerides. •Consider orlistat or octreotide for controlling the volume of effusion.
Fatigue	•Rule out other causes (e.g., anemia, hypothyroidism, malnutrition). •Consider short-term dexamethasone or methylprednisolone. •Withhold the drug in grade ≥ 3 and resume with a dose reduction.
Tumor lysis syndrome	•Prophylaxis with hydration, monitoring, and allopurinol or rasburicase in high-risk patients. •Prescribe i.v. fluid with 2–3 L/m2 of isotonic saline. •Prescribe allopurinol or rasburicase. •Correct electrolytes abnormalities and consider dialysis if refractory. •Withhold the drug until TLS is resolved and resume with dose reduction.
Reproduction	•Discuss the potential for causing infertility with the patient before starting. •Check pregnancy status in women of reproductive potential prior to initiating therapy. •For selpercatinib, prescribe effective contraception during therapy and up to one week after. For pralsetinib, prescribe non-hormonal contraception during treatment and for 2 weeks after. •Counsel the patient to abstain from breast feeding during therapy and up to 1 week after.
Hypothyroidism	•Lower T3 levels, although normal T4. •Thyroidectomized patients may need supplementation with liothyronine.