US Pharm. 2024;49(10):HS1-HS11.

New molecular entities (NMEs), as defined by the FDA, are new drug products containing as their active pharmaceutical ingredient a chemical substance marketed for the first time in the United States. The following descriptions of NMEs approved in 2023–2024 (TABLE 1) highlight the basic clinical and pharmacologic profiles for each new drug, as well as key precautions and warnings. Also included are brief summaries of selected dosing, pharmacokinetic, adverse-reaction (AR), and drug-interaction data submitted to the FDA in support of the manufacturer’s New Drug Application. This review is intended to be objective rather than evaluative in content. The information for each NME was obtained primarily from sources published prior to FDA approval. Experience clearly demonstrates that many aspects of an NME’s therapeutic profile are not detected in premarketing clinical studies and emerge after the drug is used in the broader population. For example, previously unreported ARs become apparent for some NMEs within several years of their availability. Some NMEs may even acquire at least one black box warning for serious adverse effects or be withdrawn from the market for safety reasons not recognized at the time of FDA approval. Therefore, while this review offers an introduction to certain new drugs, it is essential that practitioners be aware of changes in their therapeutic profiles as reported in the healthcare literature and by patients.


Capivasertib (Truqap, AstraZeneca)

Indication and Clinical Profile1: Capivasertib is a kinase inhibitor indicated for locally advanced or metastatic hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer that has >1 alteration of PIK3CA/AKT1/PTEN, as detected by an FDA-approved test, after >1 endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy. Capivasertib must be used in combination with fulvestrant.

The efficacy of capivasertib plus fulvestrant was established in the randomized, double-blind, placebo-controlled, multicenter CAPItello-291 trial. A total of 708 adults with locally advanced or metastatic HR-positive, HER2-negative breast cancer, 289 of whom had PIK3CA/AKT1/PTEN alterations, were enrolled. Patients were assigned to treatment with either capivasertib 400 mg orally or placebo twice daily for 4 days, followed by 3 days off treatment each week of a 28-day treatment cycle. Both groups received fulvestrant 500 mg IM on days 1 and 15 of cycle 1 and then at day 1 of all following cycles. The primary outcomes were progression-free survival (PFS) in the overall population and in patients whose tumors had PIK3CA/AKT1/PTEN alterations. Secondary outcomes included overall survival, investigator-assessed objective response rate, and duration of response. A statistical difference was found in the overall population, prompting an exploratory analysis of the nonaltered tumor population (hazard ratio [HR] 0.79 [95% CI: 0.61, 1.02]). According to the investigators, the difference was primarily due to the results seen in patients with PIK3CA/AKT1/PTEN alteration. For the PIK3CA/AKT1/PTEN-alteration population, the capivasertib group had 121 (78%) events of progression or death and a median PFS of 7.3 months, and the placebo group had 115 (86%) events and median PFS of 3.1 months (HR 0.50 [95% CI: 0.38, 0.65; P <.0001]).

Pharmacology and Pharmacokinetics1: Capivasertib (FIGURE 1) is a pyrrolo[2,3-d]pyrimidin)-4-piperidine-carboxamide that acts as a kinase inhibitor, inhibiting all three isoforms of serine/threonine kinase AKT (AKT1, AKT2, and AKT3) and blocking phosphorylation of downstream AKT substrates. Capivasertib alone and with fulvestrant was able to inhibit tumor growth of mouse xenograft models with alterations in PIK3CA, AKT1, and PTEN.


Capivasertib is predicted to reach steady-state concentrations on the 3rd and 4th dosing days of each week, starting at week 2. Steady-state AUC is 8,069 h*ng/mL (37%) and maximum concentration is 1,375 ng/mL (30%), with both showing proportionality over a dosing range of 80 mg to 800 mg. Time to maximum concentration is 1 to 2 hours and bioavailability is 29%, with no effects from high- or low-fat meals. Steady-state volume of distribution is 1,847 L (36%), and plasma protein binding is 22%. Capivasertib showed a half-life of 8.3 hours and a steady-state clearance of 50 L/h (37% coefficient of variation).

Adverse Reactions and Drug Interactions1,2: The most common (>20%) adverse reactions in capivasertib trials were diarrhea, cutaneous adverse reactions, increased random glucose, nausea and fatigue, vomiting, and stomatitis. The most common laboratory abnormalities (>20%) were decreased leukocytes, decreased lymphocytes, increased triglycerides, decreased neutrophils, increased creatinine, increased fasting glucose, and decreased hemoglobin.

Capivasertib is contraindicated in patients with severe hypersensitivity to the drug or any of its components. Warnings and precautions include hyperglycemia, diarrhea, cutaneous adverse reactions, and embryo-fetal toxicity. Capivasertib is a CYP3A substrate, and therefore coadministration with strong to moderate CYP3A4 inhibitors should be avoided, or the capivasertib dose should be reduced if coadministration cannot be avoided. Coadministration with strong or moderate CYP3A inducers should be avoided, as concurrent use may reduce drug exposure and efficacy.

Dosage and Administration1: Capivasertib is supplied as 160-mg and 200-mg tablets. The recommended dosage for adults, in combination with fulvestrant, is 400 mg orally twice daily for 4 days followed by 3 days off. Tablets should be swallowed whole 12 hours apart, with or without food. Fasting blood glucose and hemoglobin A1C should be evaluated prior to and regularly while taking this agent. Dosage modification is recommended for adverse reactions, with general modifications for first and second dose reductions. Specific modifications are proposed for hyperglycemia, diarrhea, cutaneous adverse reactions, and other adverse reactions based on the grading system in Common Terminology Criteria for Adverse Events Version 5.

Fruquintinib (Fruzaqla, Takeda)

Indication and Clinical Profile3: Fruquintinib is a kinase inhibitor indicated for treatment of adults with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti–vascular endothelial growth factor (VEGF) therapy, and, if RAS wild-type and medically appropriate, an anti–epidermal growth factor receptor (EGFR) therapy. Its efficacy was established in the FRESCO and FRESCO-2 trials, both of which were randomized, multicenter, double-blind, and placebo-controlled. The FRESCO trial was conducted in China, whereas the FRESCO-2 trial was global. Both studies enrolled patients with mCRC who had had disease progression during or after prior treatment with fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy. FRESCO-2 also included patients who had disease progression during or after prior treatment with an anti-VEGF biological therapy if RAS wild-type, an anti-EGFR biological therapy, and trifluridine/tipiracil, regorafenib, or both. The efficacy outcomes of both studies were overall survival (OS) and progression-free survival (PFS) determined according to Response Evaluation Criteria in Solid Tumors version 1.1.

Both studies randomized patients (2:1) to receive either fruquintinib 5 mg orally once daily for the first 21 days of each 28-day cycle plus best supportive care (BSC) or placebo plus BSC. In FRESCO-2 (N = 691), the median OS was 7.4 months in the fruquintinib group versus 4.8 months in the placebo group (hazard ratio [HR] 0.66 [95% CI: 0.55, 0.80; P <.001]), and PFS was 3.7 months in the fruquintinib group versus 1.8 months in the placebo group. In FRESCO (N = 416), the median OS was 9.3 months in the fruquintinib group versus 6.6 months in the placebo group (HR 0.65 [95% CI: 0.51, 0.83; P <.001]), and PFS was 3.7 months in the fruquintinib group versus 1.8 months in the placebo group (HR 0.26 [95% CI: 0.21, 0.34]).

Pharmacology and Pharmacokinetics3: Fruquintinib (FIGURE 2) is a dimethoxyquinazolin-benzofuran small molecule inhibitor that blocks VEGF receptor -1, -2, and -3, resulting in inhibition of tumor growth. Steady state is reached after 14 days, with a maximum concentration of 300 ng/mL and AUC for the dosing interval (AUC0-24h) of 5,880 ng*h/mL. Time to maximum concentration is 2 hours, the volume of distribution is 46 L, and the half-life is approximately 42 hours. Fruquintinib plasma protein binding is 95%. Metabolism occurs through CYP450 and non-CYP450 mechanisms, with CYP3A being the primary CYP enzyme. Isozymes CYP2C8, CYP2C9, and CYP2C19 also play a lesser role in metabolism of fruquintinib. Excretion is primarily through the urine (60%), but biliary excretion is also prominent (30%).


Adverse Reactions and Drug Interactions4: The most common adverse reactions (>20%) that were reported in trials were hypertension, palmar-plantar erythrodysesthesia (PPE), hypothyroidism, abdominal pain, anorexia, diarrhea, stomatitis, proteinuria, and fatigue. The most common laboratory abnormalities (>20%) were decreased serum albumin, calcium, magnesium, potassium, sodium, platelet count, and hemoglobin and increased cholesterol, glucose, triglycerides, uric acid, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bilirubin, and creatinine.

No contraindications have been reported to date. Warnings and precautions include hypertension, hemorrhagic events, infections, gastrointestinal perforation, hepatotoxicity, proteinuria, PPE, posterior reversible encephalopathy syndrome, impaired wound healing, arterial thromboembolic events, allergic reactions to the dyes FD&C Yellow No. 5 (tartrazine) and No. 6 (sunset yellow FCF), and embryo-fetal toxicity. The concomitant use of fruquintinib with strong CYP3A inducers should be avoided, and its use with moderate CYP3A inducers should be avoided when possible.

Dosage and Administration3: Fruquintinib is available as 1-mg and 5-mg capsules. The 1-mg capsules contain FD&C Yellow No. 5 and FD&C Yellow No. 6. The recommended dosing is 5 mg once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Capsules should be swallowed whole and may be taken with or without food. Fruquintinib-related adverse reactions should be addressed according to the recommended dose-reduction modifications based on reaction severity.

Repotrectinib (Augtyro, Bristol-Myers Squibb)

Indication and Clinical Profile5: Repotrectinib is a tyrosine kinase inhibitor (TKI) indicated for treatment of adults with locally advanced or metastatic ROS1-positive non–small-cell lung cancer (NSCLC). The drug has received accelerated approval for treatment of adult and pediatric patients aged >12 years with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy.

The drug’s efficacy was assessed in TRIDENT-1, a phase I/II, multicenter, single-arm, open-label, multicohort clinical trial in which 426 patients with ROS1-positive locally advanced or metastatic NSCLC received repotrectinib. Patients were excluded if they had a history of interstitial lung disease (ILD); drug-related pneumonitis; significant, uncontrolled, active cardiovascular disease; or prolonged QTc interval. Repotrectinib was dosed at 160 mg orally once daily for 14 days, then increased to 160 mg twice daily until disease progression or unacceptable toxicity. The major efficacy outcomes were overall response rate (ORR) and duration of response (DOR), and the efficacy populations included 71 TKI-naïve patients and 56 patients who received one prior ROS1 TKI. A confirmed ORR of 79% (95% CI: 68, 88) and a DOR of 34.1 months were observed in the 71 TKI-naïve patients, and the 56 patients who received one prior ROS1 TKI had a confirmed ORR of 38% (95% CI: 25, 52) and DOR of 14.8 months.

Accelerated approval for treatment of NTRK-positive solid tumors was based on TRIDENT-1 data on 88 adults with locally advanced or metastatic NTRK gene fusion–positive solid tumors who either had received a prior TKI (n = 48) or were TKI-naïve (n = 40). Patients with symptomatic brain metastases were excluded. Participants received repotrectinib 160 mg orally once daily for 14 days, then increased to 160 mg twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measures were ORR and DOR. In TKI-naïve patients (median follow-up of 17.8 months), the confirmed ORR was 58% (95% CI: 41, 73); 15% of patients experienced complete response and 43% experienced partial response. Median DOR was not evaluable (NE) (95% CI: NE, NE). Among responders, 83% had responses lasting >12 months. In TKI-pretreated patients (median follow-up of 20.1 months), the confirmed ORR was 50% (95% CI: 35, 65); of these patients, 50% experienced a partial response. Median DOR was 9.9 months (95% CI: 7.4, 13). Among responding patients, 42% were still in response at 1 year.

Pharmacology and Pharmacokinetics5: Repotrectinib (FIGURE 3), a pentaazatetracyclo-heptaen-14-one, is an inhibitor of proto-oncogene tyrosine kinase (TK) ROS1 and of the tropomyosin receptor TKs TRKA, TRKB, and TRKC. Steady state is reached within 14 days, resulting in a steady-state maximum concentration of 713 ng/mL and AUC of 7,210 ng*h/mL. Its bioavailability is 45.7%, with peak concentrations reached 2 to 3 hours after a single dose of 40 mg to 240 mg. Repotrectinib plasma protein binding is 95%, and the volume of distribution is 432 L. Metabolism is primarily through the CYP3A system, with a terminal half-life of 35.4 hours. Excretion is primarily in the feces (89%), with minimal renal excretion (5%).


Adverse Reactions and Drug Interactions5,6: The most common adverse reactions in clinical trials (≥20%) were constipation, dysgeusia, lymphocytopenia, ataxia, cognitive dysfunction, fatigue, peripheral neuropathy, and dyspnea. The most common laboratory abnormalities (≥20%) were decreased hemoglobin, lymphocytes, neutrophils, and phosphate, and increased creatine phosphokinase, gamma-glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, sodium, alkaline phosphatase, uric acid, potassium, and international normalized ratio. Serum glucose was increased in 26% of patients and decreased in 20%.

To date, there are no contraindications for repotrectinib. Warnings and precautions include central nervous system reactions, ILD/pneumonitis, hepatotoxicity, myalgia with creatine skeletal fractures, phosphokinase elevation, hyperuricemia, and embryo-fetal toxicity. Repotrectinib is a CYP3A and P-glycoprotein (P-gp) substrate as well as a CYP3A inducer. Therefore, its use should be avoided in patients currently on strong or moderate CYP3A inhibitors, P-gp inhibitors, strong or moderate CYP3A inducers, or certain CYP3A4 substrates where minimal concentration changes can cause reduced efficacy, such as hormonal contraceptives.

Dosage and Administration5: Repotrectinib is supplied as 40-mg and 160-mg capsules. The recommended dosage is 160 mg orally once daily with or without food for 14 days, then increased to 160 mg twice daily and continued until disease progression or unacceptable toxicity. Before repotrectinib initiation, strong and moderate CYP3A inhibitors should be discontinued for three to five elimination half-lives of the CYP3A inhibitor. Liver-function tests and uric acid level should be assessed prior to starting repotrectinib. The prescribing information provides recommended dosage modifications for managing repotrectinib adverse reactions.

Toripalimab-tpzi (Loqtorzi, Coherus)

Indication and Clinical Profile7: Toripalimab-tpzi is a monoclonal antibody (mAB) indicated in combination with cisplatin and gemcitabine for first-line treatment of adults with metastatic or recurrent, locally advanced nasopharyngeal carcinoma (NPC), or as a single agent for treatment of adults with recurrent unresectable or metastatic NPC with disease progression on or after a platinum-containing chemotherapy.

FDA approval of toripalimab-tpzi was based on results from JUPITER-02, a randomized, multicenter, single-region, double-blind, placebo-controlled trial, and POLARIS-02, an open-label, multicenter, multicohort trial. JUPITER-02 included patients with metastatic or recurrent, locally advanced NPC who had not received systemic chemotherapy for recurrent or metastatic disease or patients with recurrent NPC who had an interval of ≥6 months between the last dose of radiotherapy or chemotherapy and recurrence. The primary endpoint of JUPITER-02 was Blinded Independent Review Committee (BIRC)–assessed progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). The treatment group received toripalimab-tpzi 240 mg IV every 3 weeks in combination with cisplatin 80 mg/m2 on day 1 every 3 weeks and gemcitabine 100 mg/m2 on days 1 and 8 for up to six cycles, followed by toripalimab-tpzi 240 mg once every 3 weeks. The placebo group received the same regimen, with placebo substituted for the toripalimab-tpzi. The toripalimab-tpzi group had 49 events (34%) and PFS of 11.7 months, and the placebo group had 79 events (55%) and PFS of 8 months (hazard ratio 0.52 [95% CI: 0.36, 0.74; P = .0003]). Overall response rate (ORR) was 77% in the toripalimab-tpzi group versus 66% in the placebo group (P = .0353).

POLARIS-02 included 172 patients with unresectable or metastatic NPC who had received prior platinum-based chemotherapy for treatment of recurrent or metastatic NPC or had disease progression within 6 months of completion of platinum-based chemotherapy administered as neoadjuvant, adjuvant, or definitive chemoradiation treatment for locally advanced disease. The primary efficacy endpoints were confirmed ORR and duration of response (DOR) as assessed by a BIRC using RECIST v1.1. Patients received toripalimab-tpzi 3 mg/kg IV every 2 weeks until disease progression per RECIST v1.1 or unacceptable toxicity. BIRC-assessed ORR was 21% and DOR was 14.9 months.

Pharmacology and Pharmacokinetics7: Toripalimab-tpzi is a humanized mAB that binds and inhibits the programmed cell death protein 1 (PD-1) receptor located on T cells, blocking the binding of PD-1 ligands (PD-L1 and PD-L2) and thereby stimulating T-cell proliferation and cytokine production. This antagonism of the PD-1 pathway results in an antitumor immune response and decreased tumor growth.

Toripalimab-tpzi dosages of 0.3 mg/kg to 10 mg/kg every 2 weeks resulted in nonlinear concentrations. Steady state is achieved by week 7, with a mean accumulation ratio of 1.4 for maximum concentration and 1.9 for AUC. Steady-state volume of distribution was 3.7 L. Metabolism is through the protein catabolic pathways where toripalimab-tpzi is degraded into smaller peptides. First dose mean clearance was 14.9 mL/h and steady-state clearance was 9.5 mL/h. First dose mean terminal half-life was 10 days and steady-state mean half-life was 18 days. The use of toripalimab-tpzi in patients with moderate-to-severe hepatic or renal impairment has not been studied.

Adverse Reactions7,8: The most common adverse reactions (>20%) associated with toripalimab-tpzi as a single agent were hypothyroidism, fatigue, and cough. The most common laboratory abnormalities (>20%) included decreased albumin, calcium, phosphate, sodium, hemoglobin, and lymphocytes, and increased glucose, triglycerides, alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST). The most common adverse reactions (≥20%) associated with toripalimab-tpzi used in combination with cisplatin and gemcitabine were nausea, vomiting, constipation, decreased appetite, hypothyroidism, rash, pyrexia, diarrhea, peripheral neuropathy, cough, musculoskeletal pain, upper respiratory infection, insomnia, dizziness, and malaise. The most common laboratory abnormalities (>20%) in combination with cisplatin and gemcitabine were decreased hemoglobin, neutrophils, lymphocytes, platelets, magnesium, sodium, albumin, potassium, and glucose, and increased ALT, AST, lactate dehydrogenase, ALP, and creatinine.

At present, there are no contraindications for toripalimab-tpzi. Warnings and precautions include severe and fatal immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem-cell transplantation, and embryo-fetal toxicity.

Dosage and Administration7: Toripalimab-tpzi is available as a 240 mg/6 mL (40 mg/mL) single-dose vial that is clear to slightly opalescent and colorless to slightly yellow. The recommended dosing for first-line NPC is 240 mg IV every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months. For recurrent NPC, the recommended dosing is 3 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity. No dose modifications are recommended for toripalimab-tpzi, but it is recommended to hold toripalimab-tpzi for severe (Grade 3) immune-mediated adverse reactions and to permanently discontinue for life-threatening (Grade 4) immune-mediated reactions, recurrent severe (Grade 3) immune-mediated reactions requiring systemic immunosuppressive treatment, or an inability to reduce prednisone to <10 mg/day (or equivalent) within 12 weeks of initiating steroids. Toripalimab-tpzi should be injected into a 100-mL or 250-mL 0.9% Sodium Chloride Injection, USP, bag and administered with a 0.2-um or 0.22-um in-line filter. First-dose administration should be over 60 minutes, with subsequent doses reduced to 30 minutes if no infusion-related reactions were observed. If administered on the same day as chemotherapy, toripalimab-tpzi should be given prior to the chemotherapy.

REFERENCES

1. Truqap (capivasertib) product information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; November 2023.
2. Capivasertib: drug information. LexiDrugs. UpToDate Lexidrug. https://online.lexi.com. Accessed June 1, 2024.
3. Fruzaqla (fruquintinib) product information. Lexington, MA: Takeda Pharmaceuticals America, Inc; November 2023.
4. Fruquintinib: drug information. LexiDrugs. UpToDate Lexidrug. https://online.lexi.com. Accessed June 1, 2024.
5. Augtyro (repotrectinib) product information. Princeton, NJ: Bristol-Myers Squibb Co; June 2024.
6. Repotrectinib: drug information. LexiDrugs. UpToDate Lexidrug. https://online.lexi.com. Accessed June 1, 2024.
7. Loqtorzi (toripalimab-tpzi) product information. Redwood City, CA: Coherus BioSciences, Inc; April 2024.
8. Toripalimab: drug information. LexiDrugs. UpToDate Lexidrug. https://online.lexi.com. Accessed June 1, 2024.

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