Salivary Gland Carcinomas

Abiraterone acetate is an antiandrogen (androgen synthesis inhibitor) used for antihormonal therapy of prostate cancer. By inhibiting the CYP17 enzyme, it also inhibits extragonadal androgen biosynthesis in the tumor and metastases. It is administered daily in combination with 10 mg of prednisone. Side effects primarily include fatigue, hot flashes, edema, hypokalemia and hypomagnesemia, as well as constipation.

Abiraterone is a CYP3A4 substrate, meaning that CYP3A4 inducers accelerate its oxidative metabolism. Concomitant treatment with strong CYP3A4 inducers may reduce the bioavailability of abiraterone and potentially impair its efficacy. Concomitant use of CYP3A4 inhibitors does not affect plasma levels of abiraterone. An increased incidence of fractures and deaths has been observed with concomitant treatment with abiraterone and [223Ra]radium chloride. Concomitant treatment with [223Ra]radium chloride is contraindicated. Androgen deprivation therapy with abiraterone may prolong the QTc interval. Therefore, the risk of ventricular tachycardia is increased during concomitant treatment with drugs that may also prolong the QTc interval. Torsade de pointes with symptomatic dizziness or syncope may occur. In rare cases, these may progress to ventricular fibrillation and cardiac arrest. Concomitant use with drugs that prolong the QTc interval should be undertaken with great caution.

Abiraterone is a CYP2D6 inhibitor and inhibits the oxidative metabolism of CYP2D6 substrates. Abiraterone may impair the analgesic and antitussive effects of codeine and increase the bioavailability of dextromethorphan by approximately 200%. Concomitant treatment with abiraterone may enhance the effects of CYP2D6 substrates (ajmaline, amphetamines, dextromethorphan, flecainide, haloperidol, hydromorphone, metoprolol, propafenone, propranolol, risperidone, tramadol, venlafaxine). Concomitant administration of abiraterone with food increases abiraterone exposure up to 17-fold.

Amivantamab is a bispecific antibody against MET and EGFR. In a phase II study in patients with recurrent and/or metastatic adenoid cystic salivary gland carcinoma [140], it was administered at a dose of 1050 mg (for body weight < 80 kg) or 1400 mg (for ≥ 80 kg) weekly for 1 month, followed by administration on days 1 and 15 every 4 weeks until disease progression. In 18 evaluable patients, the overall response rate was 5.6% (1 PR), and a clinical benefit was observed in 72.2% overall. Acneiform skin reactions (86%), infusion-related reactions (76%), and fatigue (71%) were the most frequently documented adverse effects. The prescribing information recommends concomitant medication (glucocorticoids, antihistamines, antipyretics) when treating patients with non-small cell lung cancer (approved indication) who are receiving higher doses. Clinically relevant interactions are not expected due to the pharmacological properties of the antibody.

Avelumab is a human monoclonal IgG1 antibody. It binds to programmed cell death ligand 1 (PD-L1) and prevents its binding to its receptor PD-1. Indications include cutaneous Merkel cell carcinoma, renal cell carcinoma, and urothelial carcinoma. The most common side effects during palliative combination therapy with axitinib for adenoid cystic carcinoma of the salivary glands [111] were fatigue, diarrhea, hypertension, nausea, weight loss, and constipation, as well as skin rashes, hypothyroidism, and elevated liver enzymes, which are presumed to be autoimmune-related side effects. Concomitant administration of immunosuppressive medications is expected to impair the efficacy of avelumab.

Axitinib is a tyrosine kinase inhibitor that selectively inhibits VEGF receptors 1–3. It is approved for palliative therapy in renal cell carcinoma. Side effects primarily include hypertension, mucositis, weight loss, proteinuria, diarrhea, and fatigue. Axitinib is a tyrosine kinase inhibitor that is metabolized primarily in the liver via CYP3A4 and to a lesser extent via CYP1A2 and CYP2C19. Concomitant treatment with strong CYP3A4/5 inducers may reduce the plasma concentrations of axitinib and thereby impair its clinical efficacy. Concomitant treatment with strong CYP3A4 enzyme inhibitors may increase the plasma concentrations of axitinib and thereby also increase adverse effects. No clinically relevant study results are available regarding a possible pharmacodynamic potentiation of the side effects of axitinib by other drugs or a possible influence of axitinib on the effects of other drugs. Taking axitinib with a moderately high-fat meal resulted in a 10% reduction in bioavailability compared to administration on an empty stomach. A high-calorie meal increased bioavailability by 19%. These effects are not considered clinically significant. Concomitant use of strong CYP3A4 inhibitors or inducers with axitinib should be avoided. Throughout treatment with axitinib, consumption of grapefruit, grapefruit-like fruits (e.g., pomelo, bitter orange, clementine), and their preparations should be avoided. If concomitant treatment with axitinib and strong CYP3A4 inhibitors is unavoidable, a reduction of the axitinib dose to approximately half is recommended. If macrolide antibiotics are indicated, drugs that do not inhibit CYP3A4 or inhibit it only slightly (e.g., azithromycin) should be preferred. If a strong CYP3A4/5 inducer must be used concomitantly, it is recommended to increase the axitinib dose gradually. After discontinuation of the inducer, the reduction in the axitinib dose must be done slowly, as the inducing effects persist beyond the discontinuation of the inducer due to the half-life of the enzymes.

Bicalutamide is a nonsteroidal antiandrogen (androgen receptor antagonist) used for antihormonal therapy of prostate cancer. No adverse effects have been reported from its use as adjuvant monotherapy for androgen receptor-positive salivary gland carcinomas [75]. Common side effects according to the prescribing information include skin rashes, weight loss, weight gain, anemia, loss of appetite, diabetic metabolic disorder, loss of libido, depression, abdominal complaints such as diarrhea or constipation, elevated liver enzymes, alopecia, dry skin, sweating, itching, muscle and bone pain, chest tightness, and gynecomastia. Bicalutamide is primarily metabolized in the liver via oxidation and glucuronidation; however, the enzymes involved are unknown. Involvement of CYP3A4 appears possible. Theoretically, therefore, concomitant use of drugs that inhibit various CYP enzymes may increase plasma concentrations of bicalutamide, while inducers of CYP enzymes may decrease plasma concentrations of bicalutamide. Bicalutamide is a weak inhibitor of CYP3A4 and resulted in an increase in the bioavailability of the CYP3A4 substrate midazolam by up to 80%. This increase may be significant for CYP3A4 substrates with a narrow therapeutic range (e.g., cyclosporine). In some cases, the risk of bleeding was increased or bleeding events occurred during concomitant treatment with vitamin K antagonists and bicalutamide. It is assumed that bicalutamide displaces vitamin K antagonists from plasma protein binding. The risk of “Torsades de pointes” associated with the use of QTc-prolonging drugs may be increased by concomitant administration of bicalutamide, as androgen deprivation therapy with bicalutamide can prolong the QTc interval. Patients with risk factors for QTc prolongation should be monitored by electrocardiogram. When administering cyclosporine, careful monitoring of plasma concentrations is recommended during treatment with bicalutamide. Similarly, patients being treated concomitantly with vitamin K antagonists should be closely monitored.

Patients with risk factors for QTc prolongation should be monitored by electrocardiogram. When administering cyclosporine, careful monitoring of plasma concentrations is recommended during treatment with bicalutamide. Patients being treated concomitantly with vitamin K antagonists should also be closely monitored.

Cabozantinib is a multikinase inhibitor. In addition to VEGFR1, VEGFR2, and VEGFR3 kinases, it also inhibits AXL and MET. Cabozantinib is approved for the treatment of renal cell carcinoma, hepatocellular carcinoma, neuroendocrine tumors, and differentiated thyroid carcinoma. A phase II study in patients with salivary gland carcinomas was terminated prematurely due to excessive toxicity in the area of previously irradiated wounds [120]. The most common adverse effects leading to dose reduction in larger clinical trials with cabozantinib were diarrhea (16%), palmar-plantar erythrodysesthesia (11%), and fatigue (10%).

Cabozantinib exhibits very high plasma protein binding. As a result, it can displace other drugs that are strongly bound to plasma proteins from their plasma protein binding sites. In the case of drugs with a narrow therapeutic index, this can lead to an increase in both desired and undesired effects if their metabolic and excretion pathways are simultaneously impaired. When cabozantinib is taken with a very high-fat meal, its oral bioavailability is increased by 57% compared to when taken on an empty stomach. Cabozantinib is primarily metabolized by CYP3A4. Concomitant treatment with cabozantinib and strong CYP3A4 inducers may reduce the systemic availability of cabozantinib and thus its clinical efficacy. Concomitant treatment with cabozantinib and strong CYP3A4 inhibitors may increase the incidence of adverse effects. Concomitant treatment with cabozantinib and drugs that are strong CYP3A4 inducers or CYP3A4 inhibitors should be avoided. Throughout the entire duration of treatment with cabozantinib, patients should avoid consuming grapefruit, grapefruit-like fruits (e.g., pomelo, bitter orange), and preparations containing these fruits. Myelosuppression caused by cabozantinib, which occurs very frequently, may be exacerbated by the concomitant use of other myelosuppressive drugs. Since electrolyte disturbances have been observed very frequently during treatment with cabozantinib, concomitant treatment with cabozantinib and drugs that prolong the QTc interval may increase the risk of polymorphic ventricular arrhythmias, known as “Torsade de pointes.” During treatment with cabozantinib, attention should be paid to a possible decrease in the levels of individual or all blood cell lines. Appropriate measures should be taken if necessary. Concomitant treatment with cabozantinib and drugs that prolong the QTc interval should be avoided. If this is not possible, attention should be paid to maintaining electrolyte balance, and the QTc interval should be monitored regularly. Taking cabozantinib may lead to bleeding, which can be severe in some cases. This risk is increased by the concomitant administration of cabozantinib with anticoagulants. During concomitant treatment with cabozantinib and anticoagulants, coagulation-related laboratory parameters should be monitored regularly. Cases of gastrointestinal perforation have been reported in clinical trials. This risk may be increased by the concomitant use of cabozantinib with substances known to carry a risk of gastrointestinal perforation. Concomitant treatment with cabozantinib and drugs associated with a risk of gastrointestinal perforation should be avoided.

Carboplatin is a platinum derivative that has been used in combination with paclitaxel for palliative therapy in patients with salivary gland carcinomas [93]. Common side effects reported include neutropenia, nausea, vomiting, alopecia, diarrhea, or constipation. Neurotoxicity may also occur occasionally.

Cetuximab is a monoclonal antibody against the EGF receptor. It is approved for the treatment of colorectal carcinomas as well as head and neck squamous cell carcinomas. Side effects (grade 3–4) that occurred in more than 5% of patients in the approval studies included acneiform dermatitis and infusion reactions. Prophylactic treatment of acneiform dermatitis should be administered with doxycycline or minocycline.

Cisplatin is a platinum derivative used as palliative monotherapy [94], in conjunction with curative-intent radiotherapy, or as palliative combination therapy with docetaxel and cyclophosphamide (CAP protocol) for salivary gland carcinoma. It is approved for the treatment of testicular cancer, ovarian cancer, bladder cancer, squamous cell carcinoma of the head and neck, small-cell and non-small-cell lung cancer, bronchial carcinoma, and cervical cancer. Significant side effects reported include nausea and vomiting, nephrotoxicity, polyneuropathy, ototoxicity, hematotoxicity, electrolyte imbalances, cardiotoxicity, and diarrhea. Vaccination with live vaccines (e.g., yellow fever) is contraindicated. The prescribing information notes relevant pharmacological interactions with other active substances such as ototoxic or nephrotoxic substances, anticoagulants, anticonvulsants, or phenytoin, as well as potentiation of effects when combined with paclitaxel, docetaxel, bleomycin, vinorelbine, or cyclosporine.

Cyclophosphamide is a widely used cytotoxic chemotherapeutic agent from the alkylating agent class that is frequently employed in high-dose combination therapies and is associated with a very broad spectrum of potential side effects (see prescribing information). When used palliatively at moderate doses in combination with doxorubicin and cisplatin for the treatment of salivary gland carcinoma (CAP protocol) [91], myelotoxicity (Grade II–III neutropenia) and grade II mucositis were reported. The prescribing information notes clinically relevant drug interactions, for example with aprepitant, ciprofloxacin, azole antifungals, macrolide antibiotics, sulfonamides, prasugrel, thiotepa, ondansetron, or allopurinol. Potential cardiotoxicity should be considered when combined with anthracyclines.

Dabrafenib is a BRAF-targeted tyrosine kinase inhibitor. It is approved for the treatment of melanoma, differentiated thyroid carcinoma, and non-small cell lung cancer. A response has been reported in BRAF-mutated salivary gland carcinoma when used in combination with the MEK inhibitor trametinib [106]. In monotherapy, cutaneous side effects, including newly developed squamous cell carcinomas, fatigue, and febrile reactions, have been reported.

Dabrafenib should be taken at least one hour before a meal or as far as possible after a previous meal, both in monotherapy and in combination therapy with trametinib. If dabrafenib is taken with food, its oral bioavailability decreases by 31% compared to administration on an empty stomach. Dabrafenib exhibits very high plasma protein binding. As a result, it may displace other drugs that are strongly bound to plasma proteins from plasma protein binding. In drugs with a narrow therapeutic index, this can lead to an increase in both desired and undesired effects if their metabolic and excretion pathways are limited. Dabrafenib is metabolized by CYP2C8 and CYP3A4. The resulting active metabolites, hydroxy-dabrafenib and desmethyl-dabrafenib, are also substrates of CYP3A4. Concomitant treatment with crizotinib and strong inducers of CYP3A4 or CYP2C8 may reduce the systemic availability of dabrafenib and its active metabolites and thus their clinical efficacy. Concomitant treatment with strong inhibitors of CYP3A4 or CYP2C8 may increase the incidence of adverse effects. Concomitant administration of dabrafenib with drugs that are inducers or strong inhibitors of the enzymes CYP3A4 or CYP2C8 should be avoided. Concomitant administration of dabrafenib with drugs that are CYP3A4 substrates and have a narrow therapeutic index may therefore lead to a reduction or loss of the clinical efficacy of these drugs. If concomitant treatment with dabrafenib and drugs that are CYP3A4 substrates with a narrow therapeutic index is necessary, patients must be closely monitored for the occurrence of adverse effects.

Darolutamide is an oral androgen receptor inhibitor that has been used in salivary gland carcinoma at a dose of 600 mg p.o. twice daily, i.e., 1,200 mg/day. Frequently reported side effects include, above all, fatigue or a feeling of weakness, exhaustion, tiredness, malaise, pain in the arms or legs, skin rash, as well as laboratory abnormalities such as increased liver enzymes, particularly AST/ALT, and increased bilirubin.

Docetaxel belongs to the taxane class. In HER2-positive salivary gland carcinoma, it is used in combination with trastuzumab [99]; it is also considered for palliative therapy in combination with carboplatin or as monotherapy. It is approved for the treatment of breast cancer, gastric adenocarcinoma, non-small cell lung cancer, prostate cancer, and head and neck cancer. Severe grade 3 or 4 side effects include infections, nail changes, stomatitis, and diarrhea; grade 2 side effects include alopecia. Particularly burdensome is polyneuropathy, which may be irreversible in some cases. Common side effects such as nausea/vomiting and allergic reactions can be prevented with adequate supportive care; see Onkopedia Antiemesis.

Doxorubicin (synonym: adriamycin) is a cytotoxic chemotherapeutic agent belonging to the anthracycline class of drugs. For salivary gland carcinomas, it is used in combination with cyclophosphamide and cisplatin (CAP regimen) [90, 91]. It is approved for a wide range of malignant neoplasms (breast cancer, lung cancer, ovarian cancer, endometrial cancer, bladder cancer, sarcomas, Wilms’ tumor, thyroid cancer, neuroblastoma, Hodgkin’s and non-Hodgkin’s lymphomas, acute leukemias, multiple myeloma). In addition to cardiotoxicity (maximum cumulative total dose in adults 550 mg/m²), hematotoxicity is of particular concern. Due to its tissue-damaging effects, doxorubicin should be administered via a secure venous access.

Entrectinib is a potent inhibitor of tropomyosin receptor kinases (TRK) A, B, and C and is approved for the treatment of TRK-fusion-positive tumors as well as ROS1-mutated non-small cell lung cancer. Three cross-study analyses [97] reported the following adverse effects: taste disturbances, constipation, diarrhea, fatigue, confusion, elevated serum creatinine, paresthesias, nausea, vomiting, arthralgia, myalgia, and weight gain, as well as isolated cases of severe neurotoxicity.

Enzalutamide is a pure androgen receptor antagonist with approximately 10-fold higher androgen receptor affinity than bicalutamide, which is approved for antihormonal therapy of prostate cancer. The main side effects reported include fatigue, hypertension, hot flashes, weight loss, drowsiness, diarrhea, and edema.

Enzalutamide is primarily metabolized by CYP2C8, resulting in an active metabolite. Concomitant administration of CYP2C8 inhibitors leads to an increase in the systemic availability of enzalutamide, which may exacerbate adverse effects. Concomitant administration of CYP2C8 inducers does not result in any clinically relevant change in the systemic availability of enzalutamide. Increased formation of active metabolites is also possible (e.g., clopidogrel). The full induction potential of enzalutamide often becomes apparent only after one month, when the steady state of the clinical drug concentration of enzalutamide is reached; however, induction effects may occur even earlier. If concomitant administration of enzalutamide and drugs that are strong CYP2C8 inhibitors is necessary, the dose of enzalutamide should be reduced to 80 mg once daily (prescribing information as of May 2024).

Enzalutamide is considered a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Concomitant use of enzalutamide with drugs that are substrates of CYP3A4, CYP2C19, or CYP2C9 may lead to significant reductions in systemic availability and to a marked decrease or loss of the clinical efficacy of the drugs. When taking medications that are substrates of CYP3A4, CYP2C9, or CYP2C19 concomitantly, patients should be monitored during the first month of treatment with enzalutamide for a loss of pharmacological effect or an increase in effect due to increased formation of active metabolites. A dose adjustment may need to be considered. Due to the long half-life of enzalutamide, it should be noted that the effect on CYP enzymes may persist for one month or longer after the end of treatment.

Androgen deprivation therapy may lead to a prolongation of the QTc interval. Concomitant treatment with enzalutamide and other QTc-prolonging drugs may increase the risk of polymorphic ventricular arrhythmias, known as “Torsade de pointes.” The risk of seizures during treatment with enzalutamide is increased in patients taking medications that lower the seizure threshold. Concomitant treatment of enzalutamide with drugs that prolong the QTc interval should be avoided. If this is not possible, electrolyte balance should be maintained and the QTc interval monitored regularly.

Epirubicin is a cytotoxic chemotherapeutic agent belonging to the anthracycline class, which is approved for the treatment of breast cancer, ovarian cancer, gastric cancer, and small cell lung cancer. The most important side effects are myelosuppression and cumulative cardiotoxicity (maximum total dose 900 mg/m² epirubicin hydrochloride according to the prescribing information). In a study on the palliative treatment of salivary gland carcinoma [95], the following adverse effects were reported: alopecia, nausea, vomiting, mucositis, and a tissue reaction at the peripheral venous access site.

Goserelin is a GnRH analog used for antiandrogen therapy in prostate cancer. It is administered subcutaneously under the abdominal skin every 3 months. No adverse effects were reported from palliative monotherapy in androgen receptor-positive salivary gland carcinomas [75]. The most common side effects, according to the prescribing information, are impaired glucose tolerance, loss of libido, heart failure, hot flashes, sweating, skin rashes, bone pain, erectile dysfunction, and local reactions at the injection site.

Larotrectinib is a selective TRK inhibitor approved for the treatment of TRK-fusion-positive tumors. A study on its use in salivary gland carcinomas [96] reported the following side effects: elevated liver enzymes, confusion, constipation, fatigue, muscle and joint pain, nausea, edema, headaches, weight gain, hyperglycemia, and peripheral neuropathy. The prescribing information notes that if concomitant administration with a strong CYP3A4 inhibitor is necessary, the dose should be reduced by 50%. After discontinuing the inhibitor for 3 to 5 elimination half-lives, treatment should be resumed at the dose taken prior to treatment with the CYP3A4 inhibitor.

Lenvatinib is a multi-tyrosine kinase inhibitor that inhibits VEGFR1-3, FGFR1-4, PDGF, KIT, and RET. In a study on palliative use in adenoid cystic salivary gland carcinomas [107], the most commonly reported side effects were hypertension and oral pain; 18 of 32 patients discontinued treatment due to drug-related side effects. According to the prescribing information, other potential side effects include proteinuria, hepatotoxicity, aneurysms, aortic dissections, renal failure, diarrhea, CNS toxicity, fistulas/perforations, bleeding, arterial thromboembolism, impaired wound healing, osteonecrosis of the jaw, thyroid dysfunction, and cardiac dysfunction such as QTc prolongation may occur.

Myelosuppression caused by lenvatinib may be exacerbated by the concomitant use of other myelosuppressive drugs. Since prolongations of ventricular repolarization have been observed during treatment with lenvatinib, the concomitant administration of lenvatinib with drugs that prolong the QTc interval may increase the risk of polymorphic ventricular arrhythmias, known as “torsade de pointes.” Concomitant treatment with lenvatinib and QTc-prolonging drugs should be avoided. If this is not possible, electrolyte balance should be maintained and the QTc interval monitored regularly. Bleeding also occurs very frequently with the use of lenvatinib. Concomitant treatment with lenvatinib and anticoagulants may further increase the risk of bleeding. When lenvatinib is administered concomitantly with anticoagulants, coagulation-related laboratory parameters should be monitored regularly. Renal dysfunction, particularly acute renal failure, frequently occurs during treatment with lenvatinib. Concomitant administration of lenvatinib and drugs that interfere with the renin-angiotensin-aldosterone system (RAAS) may result in an increased risk of acute renal failure. Renal function should be monitored regularly when lenvatinib is administered concomitantly with drugs that affect the RAAS. The administration of corticosteroids or NSAIDs during therapy with lenvatinib should be avoided.

Gastrointestinal perforations have been observed during treatment with lenvatinib. The risk of this may increase with the concomitant administration of lenvatinib and drugs that interfere with prostaglandin metabolism (e.g., NSAIDs, corticosteroids).

Lenvatinib is primarily metabolized via oxidation by aldehyde oxidase. N-demethylation via CYP3A4 and glutathione conjugation represent minor metabolic pathways. Therefore, neither CYP3A4 inhibitors nor CYP3A4 inducers have a significant effect on the systemic availability of lenvatinib.

Leuprorelin is a GnRH analog used for antiandrogenic therapy of prostate cancer. It is administered subcutaneously every 6 months. No adverse effects have been reported from monotherapy in androgen receptor-positive salivary gland carcinomas [75]. The most common side effects, according to the prescribing information, are skin rashes, nasopharyngitis, hot flashes, nausea, diarrhea, enteritis, itching, night sweats, bone/joint/muscle pain, urinary retention, dysuria, anemia, prolonged clotting time, chest tightness, gynecomastia, erectile dysfunction, loss of libido, and local reactions at the injection site.

Leuprorelin may lead to QTc interval prolongation. In patients with a history of QTc prolongation or risk factors for QTc prolongation, and in patients who are concurrently taking medications that may prolong the QTc interval, physicians should weigh the benefit-risk ratio, including the potential for torsades de pointes tachycardia, before initiating treatment with leuprorelin. Regular monitoring of ECG and electrolytes should be considered.

Nivolumab is a monoclonal anti-PD-1 antibody and belongs to the class of immune checkpoint inhibitors. It is approved as monotherapy or combination therapy for the treatment of melanoma, lung cancer, pleural mesothelioma, renal cell carcinoma, Hodgkin’s disease, head and neck squamous cell carcinoma, urothelial carcinoma, colorectal carcinoma, esophageal carcinoma, and gastric carcinoma. In a study on palliative nivolumab monotherapy for salivary gland carcinoma [88], the most commonly reported adverse events were anemia, hypoalbuminemia, hyperkalemia, elevated liver enzymes, heart failure, elevated serum amylase, hyponatremia, elevated creatine phosphokinase, and renal dysfunction. Other possible side effects include rash, diarrhea, and loss of appetite, as well as sometimes severe fever and interstitial pneumonia (immune-mediated pneumonitis), and immune-mediated liver or kidney inflammation and endocrinopathies. Concomitant administration of immunosuppressive medications is expected to impair the efficacy of nivolumab.

Like docetaxel, paclitaxel belongs to the class of cytotoxic chemotherapeutic agents known as taxanes. It is approved for the treatment of breast cancer, ovarian cancer, non-small cell lung cancer, or AIDS-associated Kaposi’s sarcoma. Since it has not demonstrated efficacy as a monotherapy for salivary gland carcinomas, it is generally used in combination with carboplatin or cetuximab [92, 93]. Severe side effects may include infections, stomatitis, and diarrhea, as well as allergic reactions to the solvent Cremophor contained in the formulation. Premedication with glucocorticoids, H2-receptor antagonists, and antihistamines is mandatory. Among the debilitating side effects is alopecia; additionally, polyneuropathy—which may be irreversible in some cases—is particularly severe.

The metabolism of paclitaxel is partly catalyzed by the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Therefore, special caution is warranted when paclitaxel is used in combination with other drugs that inhibit either CYP2C8 or CYP3A4 (e.g., azole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir), as paclitaxel toxicity may be increased due to higher paclitaxel exposure. The use of paclitaxel in combination with other drugs that induce either CYP2C8 or CYP3A4 (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended, as efficacy may be impaired due to reduced paclitaxel exposure.

Pembrolizumab is an immune checkpoint inhibitor. It is a fully human monoclonal antibody of the immunoglobulin G4 (IgG4) class that binds to the PD-1 receptor on T cells and prevents interaction with the PD-1 receptor ligand that would normally bind there. It is approved for the treatment of melanoma, lung cancer, pleural mesothelioma, renal cell carcinoma, Hodgkin’s disease, head and neck squamous cell carcinoma, urothelial carcinoma, colorectal cancer, esophageal cancer, and gastric cancer. It is also approved as monotherapy for colorectal carcinoma, endometrial carcinoma, gastric carcinoma, small intestine carcinoma, and biliary carcinoma with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). In patients with salivary gland carcinoma, it has been used in studies as monotherapy or in combination with radiation therapy. No relevant pharmacological interactions have been reported. Concomitant administration of immunosuppressive medications is expected to impair the efficacy of pembrolizumab. As with other immune checkpoint inhibitors, there is a risk of immune-mediated, sometimes severe adverse effects such as pneumonitis, endocrinopathy, nephritis, hepatitis, colitis, or skin reactions.

Pertuzumab is a humanized antibody targeting HER2, approved for use in combination with trastuzumab and docetaxel in HER2-positive breast cancer. As part of a “basket” study, it was used in combination with trastuzumab in patients with salivary gland carcinomas [102]. According to the prescribing information, the order of administration is arbitrary. In addition to an infusion reaction, left ventricular dysfunction may occur as a side effect when pertuzumab is administered in combination with trastuzumab. Regular monitoring of left ventricular heart function via echocardiography should be performed during ongoing therapy. Another serious side effect may be diarrhea, which can be severe in some cases. No relevant pharmacological interactions have been reported.

Selpercatinib is a highly selective RET kinase inhibitor. It is approved across tumor types for the treatment of RET-fusion-positive tumors as well as for RET-mutated thyroid carcinomas. The main adverse effects in the cross-entity phase I/phase II study [104] were hypertension and elevated liver enzymes, along with fatigue, proteinuria, and abdominal discomfort. Severe treatment-related adverse effects were reported in 40% of patients. The prescribing information also lists pneumonia, hypersensitivity reactions, headaches, QTc prolongation, bleeding, interstitial pneumonitis, gastrointestinal symptoms such as nausea, vomiting, diarrhea, or constipation, edema, and myelosuppression as common adverse effects. In patients with known QTc prolongation, specific cardiac evaluations are recommended prior to the use of selpercatinib (see prescribing information). Due to its metabolism via CYP3A4 and P-glycoprotein, as well as its effect on CYP2C8, selpercatinib has numerous interactions with other medications and active ingredients (St. John’s wort), and its absorption following oral administration is influenced by proton pump inhibitors (PPIs). Please refer to the detailed information in the prescribing information regarding this.

Sorafenib is a multi-kinase inhibitor that inhibits the RAF and VEGF signaling pathways, as well as PDGFR-alpha and -beta, KIT, and RET. It is approved for the treatment of renal cell carcinoma, hepatocellular carcinoma, and differentiated thyroid carcinoma. In palliative monotherapy for patients with salivary gland carcinomas [108], grade ≥ 3 adverse effects were reported in nearly 30% of cases, primarily skin rashes, hand-foot syndrome, mucositis, pulmonary infections, fatigue, arterial thrombosis, and gastrointestinal complaints. Sorafenib has been extensively studied for its potential for pharmacological interactions (see prescribing information). Of particular clinical relevance is the interaction with CYP3A4 inducers such as St. John’s wort, phenytoin, dexamethasone, or carbamazepine, which can lead to a reduction in sorafenib bioavailability.

Trametinib is an orally administered MEK inhibitor that is approved in combination with the BRAF inhibitor dabrafenib for the treatment of BRAF V600-mutated melanomas, as well as NSCLC and differentiated thyroid carcinoma. This combination has also been used sporadically in patients with BRAF V600-mutated salivary gland carcinomas [106]. Trametinib monotherapy is not effective for the aforementioned tumor types. The prescribing information notes potential side effects such as QTc prolongation, reduced left ventricular ejection fraction, hypertension, fever, or visual disturbances, and mentions interstitial pneumonitis as a specific potential complication.

Trametinib is deacetylated by hydrolytic enzymes such as carboxylesterase. Due to this metabolism, an interaction via other metabolizing enzymes (e.g., CYP enzymes) is considered rather unlikely. Bleeding may occur with the use of trametinib. Concomitant treatment with trametinib and anticoagulants may further increase the risk of bleeding. When trametinib is used concomitantly with anticoagulants, coagulation-related laboratory parameters should be monitored regularly. If trametinib is taken with a high-fat, high-calorie meal, the maximum plasma concentration decreases by 70% compared to administration on an empty stomach, and oral bioavailability is reduced by 10%. Trametinib should be taken on an empty stomach, which means at least one hour before a meal or as long as possible after a previous meal.

Trastuzumab is a humanized monoclonal antibody that binds to the epidermal growth factor receptor HER2 on the cell surface, thereby inhibiting cell growth. It is approved for the treatment of HER2-positive breast cancer or gastric cancer. In a study on palliative therapy in combination with docetaxel for the treatment of HER2-positive salivary gland carcinomas [99], the most common side effects described were myelosuppression, febrile neutropenia, hypoalbuminemia, edema, elevated liver enzymes, weight loss, fatigue, constipation, and electrolyte imbalances. The prescribing information also lists skin rashes, respiratory tract infections, hypersensitivity reactions, muscle and joint pain, impaired renal function, conjunctivitis, hot flashes, and respiratory complaints as common side effects. Particular attention should be paid to cardiac dysfunction such as left heart failure and arrhythmias.

Clinically significant pharmacological interactions with other medications and active ingredients were not observed in studies.

Trastuzumab emtansine (T-DM1) is an anti-HER2 antibody-drug conjugate linked to an antimicrotubular agent. It is approved for the treatment of HER2-positive breast cancer. In the treatment of HER2-positive malignancies [100] in the NCI-MATCH study, a relevant clinical response was observed in HER2-positive salivary gland carcinomas. The most common side effects reported were anemia, thrombocytopenia, fatigue, nausea/vomiting, elevated liver enzymes, and weight loss. The prescribing information also lists urinary tract infections, headaches, polyneuropathy, sleep disturbances, gastrointestinal complaints, muscle and joint pain, and a tendency to bleed. Interstitial pneumonitis is described as a rare, sometimes severe side effect.

Trastuzumab emtansine is metabolized primarily via CYP3A4 and, to a lesser extent, via CYP3A5. Drugs that inhibit CYP3A4, e.g., azole antifungals, clarithromycin, telithromycin, and numerous antiviral agents—particularly those used for HIV treatment—should not be administered concomitantly with trastuzumab emtansine whenever possible.

Trastuzumab deruxtecan is an anti-HER2 antibody-drug conjugate; the conjugated drug is a topoisomerase inhibitor. In the multi-entity phase II study evaluating its use in HER2-positive tumors [103], a response rate of 42% was reported among 19 enrolled patients with salivary gland carcinoma. Approval currently covers the treatment of HER2-positive breast cancer, lung cancer, and gastric cancer (as of January 2024). In the USA, there is a cross-entity (“tumor-agnostic”) approval for the treatment of HER2-positive tumor diseases.

When using a dosage of 5.4 mg/kg every 3 weeks, grade 3–4 adverse effects were observed in 40% of patients, primarily nausea/vomiting, anemia, diarrhea, fatigue, loss of appetite, weight loss, and alopecia. A particular side effect is interstitial pneumonitis, which can be life-threatening and has been documented in 10–30% of treated patients in studies involving patients with various underlying malignant conditions. In these studies, however, T-DXd was also administered in some cases at a higher dosage (6.4 mg/kg every 3 weeks).

Clinically relevant pharmacological interactions with other active substances have not been identified in studies to date. The prescribing information also contains no references to such interactions.

Triptorelin is a GnRH analog used for antiandrogen therapy in prostate cancer. Outside of malignant diseases, it is approved in adults for hormone therapy in endometriosis or uterine myomatosis. It is administered subcutaneously or by deep intramuscular injection every 4 weeks. Adverse effects were not reported in detail in a study on combination therapy with bicalutamide for androgen receptor-positive salivary gland carcinomas [113]. The most common side effects, according to the prescribing information, are hypersensitivity, loss of libido, depression, sleep disturbances, hot flashes, nausea, sweating, bone/joint/muscle pain, erectile dysfunction, gynecomastia, or local reactions at the injection site.

Due to a potential QTc prolongation, concomitant administration with active substances such as quinidine, disopyramide, amiodarone, sotalol, methadone, moxifloxacin, or neuroleptics should be carefully evaluated according to the prescribing information.

Vinorelbine is a cytotoxic chemotherapeutic agent belonging to the class of vinca alkaloids, which blocks mitosis by inhibiting the formation of microtubules and the spindle apparatus. It is approved for the treatment of lung and breast cancer. In a phase II study on palliative use in salivary gland carcinomas [90], the adverse effects reported included myelosuppression, nausea/vomiting, peripheral neurotoxicity, and alopecia. According to the prescribing information, the most common side effects to note include bone marrow depression with neutropenia, anemia, and thrombocytopenia; gastrointestinal toxicity with nausea, vomiting, diarrhea, mucositis, and constipation; as well as fatigue and fever. It is important to emphasize that vaccination with live vaccines is contraindicated during treatment with vinorelbine. In addition, there are complex and, in some cases, life-threatening interactions with other active substances such as triazole antifungals, macrolide antibiotics, St. John’s wort, HIV-targeted protease inhibitors, rifampicin, carbamazepine, phenytoin, and others; therefore, before starting treatment with vinorelbine, the prescribing information must be reviewed with particular care in this regard.