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Pharmacy Forum

This monthly column focuses on noteworthy treatments and provides important information to assist oncologists in their day-to-day practice. Janelle E. Mann, PharmD, BCOP, is an Ambulatory Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column editor. Oncology Times Clinical Advisory Editor Ramaswamy Govindan, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology and Director, Section of Medical Oncology, Washington University School of Medicine, St. Louis, Mo., is the Pharmacy Forum column physician advisor.

Thursday, September 22, 2022

By Sasha Haarberg, PharmD, BCOP​

What is dostarlimab-gxly?

Dostarlimab is an anti-PD-1 humanized IgG4 monoclonal antibody. It inhibits programmed cell death 1 (PD-1) activity through binding to the PD-1 receptor located on T cells to block PD-L1 and PD-L2 ligands from binding. Blocking the PD-1 pathway leads to negative immune regulation caused by PD-1 receptor signaling.

Dostarlimab is initially FDA-approved for patients with advanced or recurrent solid tumors with the presence of deficient mismatch repair (dMMR) that have progressed on or following prior treatment, and who have no satisfactory alternative treatment options. Dostarlimab obtained an additional FDA approval for recurrent or advanced endometrial cancer that has progressed on or following a prior platinum-containing regimen and has the presence of dMMR, detected by an FDA-approved test.

What is the basis for this approval?

Dostarlimab was approved with accelerated approval in solid tumors with dMMR based on the results of the GARNET trial—specifically cohort F. This trial was a non-randomized, multicenter, open-label, multi-cohort trial. Patients received dostarlimab 500 mg intravenously every 3 weeks for 4 doses, followed by 1,000 mg every 6 weeks until disease progression. Cohort F enrolled patients with dMMR or POLEmut non-endometrial solid tumors with 99 of the 106 patients having gastrointestinal tumors. The primary efficacy endpoints included overall response rate (ORR) and duration of response (DOR). The confirmed ORR was 38.7 percent with a complete response rate of 7.5 percent. The median DOR was not reached (J Clin Oncol 2021; doi: 10.1200/JCO.2021.39.3_suppl.9).

Cohort A1 in the GARNET trial evaluated dostarlimab for patients with dMMR recurrent or advanced endometrial cancer who progressed on or after platinum-containing treatment. They enrolled 71 patients with advanced endometrial cancer with dMMR. The confirmed ORR was 42.3 percent with a complete response rate of 12.7 percent and a partial response rate of 29.6 percent. The observed median DOR was not reached (JAMA Oncol 2020;6(11):1766-1772).

How do you administer dostarlimab-gxly?

Dostarlimab is infused intravenously over 30 minutes. It is administered as a 500 mg dose every 3 weeks for the first 4 doses, followed by 1,000 mg every 6 weeks.

Are there any pre-medications needed?

Dostarlimab has a minimal emetic risk. No routine pre-medications are recommended.

What are the common side effects (> or =10%)?

The following side effects are reported for dostarlimab:

  • Gastrointestinal: constipation (16-20%), decreased appetite (12-14%), diarrhea (25-26%), nausea (22-30%), vomiting (17-18%)
  • Dermatologic: pruritus (15%), skin rash (14%)
  • Increased lab values: aspartate aminotransferase (16-26%), alanine aminotransferase (15-22%), alkaline phosphatase (25-26%), serum creatinine (21-27%), calcium (6-15%), potassium (14%)
  • Genitourinary: urinary tract infection (13%)
  • Neuromuscular & Skeletal: asthenia (</=48%), myalgia (12%)
  • Hematologic: lymphocytopenia (33-37%), anemia (24-30%), decreased neutrophils (12%), leukopenia (18-21%)
  • Respiratory: cough (13-14%)
  • Decreased lab values: albumin (26-30%), magnesium (16%), potassium (14-15%), sodium (21-26%)
  • Other: fatigue (</= 48%), fever (12%)

What are the uncommon side effects (less than 10%)?

Sepsis, erythema of skin, pemphigoid, severe abdominal pain, pancreatitis, iridocyclitis, uveitis, acute kidney injury, interstitial nephritis, pneumonitis, infusion-related reaction, and immune-mediated toxicities.

What serious warning and precautions exist for dostarlimab-gxly?

The risk of immune-mediated toxicities exists with dostarlimab. These can be serious and include pneumonitis, colitis, hepatitis, as well as multiple endocrinopathies.

Are there any important drug interactions I should be aware of?

Coadministration with corticosteroids may diminish therapeutic effects of immune checkpoint inhibitors.

How do I adjust the dose in the setting of renal or hepatic insufficiency?

No dose adjustments are provided for those with mild or moderate renal or hepatic dysfunction prior to treatment initiation. Patients experiencing renal or hepatic toxicity during treatment should be assessed for immune-mediated toxicities and managed as indicated per guidelines.

What should my patients know about dostarlimab-gxly?

  • The Ventana MMR RxDx Panel was simultaneously approved as a companion diagnostic device to select patients with dMMR solid tumors for dostarlimab treatment.
  • Pregnancy should be avoided due to the risk for embryo-fetal toxicity and both men and women should use effective contraception during treatment and at least 4 months following the last dose.
  • Breastfeeding should be avoided during treatment and at least 4 months after the last dose.

What else should I know about dostarlimab-gxly?

Immune-mediated toxicities can occur while on therapy and warrant early intervention with steroids and holding therapy based on degree of toxicity. Patients should be educated on toxicities such as adrenal insufficiency, hypophysitis, thyroid disorders, diabetes mellitus, diarrhea/colitis, myocarditis, pneumonitis, rash/dermatologic toxicity, neurotoxicity, and ocular disorders.

What useful links are available?

Any ongoing clinical trials related todostarlimab-gxly?

Dostarlimab is also being studied in clinical trials of various phases and combinations in patients with advanced cancers. More information is available about these trials at clinicaltrials.gov.

Sasha Haarberg, PHARMD, BCOP, is Clinical Oncology Pharmacist at the Siteman Cancer Center and Washington University School of Medicine, St. Louis, Mo.​​

Monday, August 22, 2022

By Alexandra Lovell, PharmD, BCOP​​

What is brexucabtagene autoleucel?

Brexucabtagene autoleucel is a modified autologous chimeric antigen receptor (CAR) T-cell immunotherapy. A patient's own T cells are harvested and genetically modified ex vivo to express a CAR targeting CD19. The anti-CD19 CAR includes a murine anti-CD19 single-chain variable fragment linked to CD28 and CD3-zeta costimulatory domains.

How does brexucabtagene autoleucel work?

Brexucabtagene autoleucel binds to cancer cells expressing CD19 and normal B cells. Once the CAR-T cells are engaged, the CD28 and CD3-zeta costimulatory domains activate downstream signaling cascade to cause T-cell activation, proliferation, acquisition of effector functions, and secretion of inflammatory cytokines and chemokines. This leads to the killing of cells that express CD19.

What is this approved for?

Brexucabtagene autoleucel is FDA-approved for treatment of adults with relapsed or refractory mantle cell lymphoma (MCL) or B-cell acute lymphoblastic leukemia (ALL).

What is the basis for this approval?

The ZUMA-2 and ZUMA-3 trials evaluated brexucabtagene autoleucel in relapsed/refractory MCL and ALL, respectively. In ZUMA-2, 60 efficacy-evaluable patients with MCL had a median of three prior lines of therapy (N Engl J Med 2020; doi: 10.1056/NEJMoa1914347). The overall response rate was 85 percent with a complete remission rate of 62 percent and a median time to response was 28 days. The median duration of response was not reached after a median of 12 months of follow-up. In ZUMA-3, 52 percent of the 54 evaluable patients with ALL achieved complete response (Lancet 2021; doi: 10.1016/S0140-6736(21)01222-8). With a median of 7 months of follow-up, the median duration of complete response was not reached. Median time to complete response was 56 days. Notably, patients with CNS disease were excluded from ZUMA-3.

How do you administer this drug?

Brexucabtagene autoleucel is given by intravenous infusion. It is for autologous use only and the patient identity should be verified against the identifiers on the cassette and infusion bag. The product must be thawed and administered over 30 minutes once thawed.

Are there any pre-medications needed?

The patient should receive lymphodepleting chemotherapy (fludarabine and cyclophosphamide) in the days prior to the infusion. Pre-medications include acetaminophen and diphenhydramine or another H1-antihistamine 30-60 minutes prior to infusing the cells.

What are the common side effects associated with brexucabtagene autoleucel (> or =20%)?

The most common adverse events are fever, cytokine release syndrome (CRS), neurologic toxicities, prolonged cytopenias, hypotension, encephalopathy, fatigue, tachycardia, arrhythmia, infection, febrile neutropenia, chills, hypoxia, cough, tremor, musculoskeletal pain, headache, nausea, edema, motor dysfunction, constipation, diarrhea, decreased appetite, dyspnea, rash, insomnia, pleural effusion, and aphasia.

What are the uncommon side effects associated with brexucabtagene autoleucel (less than 20%)?

Coagulopathy, hypersensitivity reactions, abdominal pain, mouth pain, dysphagia, cerebral edema, hypogammaglobulinemia, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, aphasia, dizziness, delirium, anxiety, renal insufficiency, thrombosis, and secondary malignancies have been reported.

Are there any important drug interactions I should be aware of?

There are no drug interactions; however, systemic corticosteroids should be avoided unless used for management of toxicity as they may interfere with the activity of brexucabtagene autoleucel.

How do I adjust the dose in the setting of renal or hepatic insufficiency?

No dose adjustments are needed in patients with renal dysfunction or hepatic impairment, although these patients were not studied. The recommended target dose is 2 x 106 and 1 x 106 CAR-positive T cells per kilogram body weight for MCL and ALL, respectively.

What should my patients know about brexucabtagene autoleucel?

  • Brexucabtagene autoleucel is made from cells from each individual patient. The patient's blood will be collected a few weeks prior to the infusion in a process called leukapheresis. Prior to receiving brexucabtagene autoleucel, patients will receive 3 days of chemotherapy.
  • Patients should be monitored at a certified health care facility daily for at least 7 days after the infusion for MCL and 14 days for ALL. Side effects can occur weeks after the infusion. Patients must be in close proximity of the health care facility for at least 4 weeks and avoid driving or operating heavy machinery for 8 weeks after the infusion. Patients should always carry the brexucabtagene autoleucel wallet card on them.
  • Patients should contact their doctor immediately if they experience fever, infection, chills, difficulty breathing, dizziness or lightheadedness, confusion, or difficulty speaking.

What else should I know about brexucabtagene autoleucel?

Brexucabtagene autoleucel requires each institution that administers it to be enrolled in a Risk Evaluation and Mitigation Strategy (REMS) program. Important aspects of this include having tocilizumab on site and immediately accessible for the treatment of CRS. Additionally, all health care providers involved in the prescribing, dispensing, and administration of brexucabtagene autoleucel are trained in the management of CRS and neurologic toxicities. The full requirement for the REMS program can be found at https://bit.ly/3vfwZWI.

What useful links are available for this drug?

  • Drug Information: https://bit.ly/3BgQvG5
  • Safety Information: https://bit.ly/3Bpi1RT
  • FDA Approval: https://bit.ly/3S5Wgw4  

Any ongoing clinical trials related to brexucabtagene autoleucel?

Brexucabtagene autoleucel is also being studied in pediatric and adolescent patients with relapsed or refractory ALL or B-cell non-Hodgkin lymphoma. More information is available at clinicaltrials.gov.​

Alexandra Lovell, PHARMD, BCOP, is Clinical Pharmacy Specialist in Leukemia at the University of Texas MD Anderson Cancer Center in Houston. 

Wednesday, July 20, 2022

By Janelle E. Mann, PharmD, BCOP

What is sirolimus protein-bound particles?

Sirolimus protein-bound particles are sirolimus formulated as albumin-bound nanoparticles. Sirolimus inhibits mammalian (mechanistic) target of rapamycin (mTOR). Sirolimus protein-bound particles are approved for adults with unresectable or metastatic malignant perivascular epithelioid cell tumors (PEComas).

Sirolimus protein-bound particles inhibit mTOR, which controls key cellular processes such as cell survival, growth, and proliferation, and is commonly dysregulated in human cancers. Sirolimus forms immunosuppressive complexes (sirolimus–FKBP12 complex), which binds to and inhibits activation of mTOR complex 1. Additionally, intravenous (IV) administration of nanoparticle protein bound sirolimus has shown higher intratumor accumulation, greater mTOR inhibition, and higher tumor growth inhibition compared to oral mTOR inhibitors.

What is this approved for?

Sirolimus protein-bound particles for injectable suspension have been FDA-approved for adults with locally advanced unresectable or metastatic malignant PEComa. The application was granted Priority Review, Fast Track Designation, Breakthrough Therapy Designation, and Orphan Drug Designation.

What is the basis for this approval?

Sirolimus protein-bound particles received approval for unrescetable or metastatic malignant PEComa based on results from the AMPECT trial (J Clin Oncol 2021;39:3660-3670). The trial was a multicenter, Phase II, single-arm, registration trial of sirolimus protein-bound particles at 100 mg/m2 given as an IV on Days 1 and 8 every 21 days to patients with locally advanced unresectable or metastatic PEComa.
A total of 34 patients were treated and included in the safety evaluation, and 31 patients were evaluable for efficacy. The primary endpoint was objective response rate with key secondary endpoints, including duration of response, progression-free survival (PFS), and safety. The observed overall response rate was 39 percent (12 of 31; 95% CI: 22-58) with one complete and 11 partial responses; 52 percent of patients had stable disease. Median duration of response was not reached after a median follow-up of 2.5 years, 7 of 12 responders with treatment ongoing (5.6-47.2+ months). The median PFS was 10.6 months (95% CI: 5.5 months to not reached), and median overall survival was 40.8 months (95% CI: 22.2 months to not reached).

How do you administer this drug?

The dosage of sirolimus protein-bound particles includes 100 mg/m2 given IV on Days 1 and 8 every 21 days until disease progression or unacceptable toxicity. Predefined dose reductions are as follows: 75 mg/m2, followed by 56 mg/m2, followed by 45 mg/m2, and then permanently discontinue if unable to tolerate 45 mg/m2. The infusion is administered over 30 minutes.

Are there any premedications needed?

No premedications are required for sirolimus protein-bound particles; however; it is associated with moderate emetic potential and routine antiemetics are required to prevent nausea and vomiting.

What are the common side effects (> or =10%)?

The following side effects are reported for sirolimus protein-bound particles:

  • Gastrointestinal: abdominal pain (29%), constipation (24%), decreased appetite (44%), diarrhea (47%), dysgeusia (32%), hemorrhoids (12%), nausea (50%), stomatitis (79%), vomiting (32%), xerostomia (15%)
  • Dermatologic: Alopecia (24%), nail disease (12%), pruritus (18%), skin rash (68%), xeroderma (12%)
  • Increased lab values: aspartate aminotransferase (AST) (32%), alanine aminotransferase (ALT) (47%), alkaline phosphatase (29%), serum lipase (12%), serum glucose (12%), serum cholesterol (48%), serum potassium (44%), serum sodium (12%), serum triglycerides (52%), serum creatinine (82%)
  • Infection: infection (59%, urinary tract infection, upper respiratory infection, and sinusitis), serious infection (12%)
  • Nervous system: dizziness (12%), fatigue (68%), headache (29%), insomnia (21%), peripheral neuropathy (15%)
  • Neuromuscular and skeletal: musculoskeletal pain (47%)
  • Hematologic: anemia (68%), decreased white blood cell count (41%), hemorrhage (24%), lymphocytopenia (82%), neutropenia (35%), thrombocytopenia (35%)
  • Respiratory: cough (35%), dyspnea (12%), interstitial pulmonary disease (≤18%), pneumonitis (≤18%)
  • Decreased lab values: serum albumin (35%), serum calcium (15%), serum glucose (15%), serum magnesium (42%), serum phosphate (15%), serum sodium (24%), serum potassium (44%)
  • Other: blurred vision (12%), fever (24%)

What are the uncommon side effects (less than 10%)?

Acute coronary syndrome, edema, enteritis, pancytopenia, upper gastrointestinal hemorrhage, and acute kidney injury occurred in less than 10 percent of patients on sirolimus protein-bound particles.

Are there any important drug interactions I should be aware of?
Sirolimus protein-bound particles are a major substrate of CYP3A4 as well as P-gp and concomitant use with strong CYP3A4 and/or P-pg inhibitors or inducers should be avoided. Additionally, concomitant use of sirolimus protein-bound particles with moderate-to-weak CYP3A4 inhibitors will require a dose reduction of sirolimus protein-bound particles.

How do I adjust the dose in the setting of renal or hepatic insufficiency?

There are no recommended dose adjustments for renal impairment and mild-to-moderate renal impairment did not significantly effect sirolimus pharmacokinetics. For mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN or total bilirubin >1-1.5 times ULN and any AST), an initial dose reduction of sirolimus to 75 mg/m2 with close monitoring for increased toxicity is recommended. Moderate hepatic impairment (total bilirubin >1.5-3 times ULN and any AST) requires an initial dose reduction to 56 mg/m2 with close monitoring. Patients with severe impairment should avoid sirolimus protein-bound particles.

What should my patients know about sirolimus protein-bound particles?

  • Treatment with sirolimus should be held for hemoglobin less than 8 g/dL and/or absolute neutrophil count less than 1,500/mm3, and/or platelets less than 100,000/mm3. Based on the grade of hematologic toxicity, dose reductions may be warranted.
  • Use of sirolimus protein-bound particles has been associated with hypokalemia and may require potassium supplementation to avoid unnecessary dose reductions; however, if patients develop Grade 2 or greater hypokalemia, a dose reduction may be needed.
  • Prior to starting sirolimus, a fasting blood glucose should be obtained followed by every 3 months for non-diabetic patients and more frequently in diabetic patients.

What else should I know about sirolimus protein-bound particles?

  • Sirolimus protein-bound particles may cause hypersensitivity as conventional oral sirolimus has been associated with anaphylaxis, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis. Additionally sirolimus protein-bound particles contain albumin, which is associated with hypersensitivity. Monitor for signs and symptoms of hypersensitivity during the infusion and for at least 2 hours after the first infusion and then as clinically necessary for subsequent infusions.
  • Sirolimus protein-bound particles are associated with stomatitis, which occurred in 79 percent of patients, including Grade 3 stomatitis. Most cases were reported within 8 weeks of starting treatment. Early identification and intervention is needed to avoid significant complications.
  • Sirolimus protein-bound particles may impair fertility in females and males and it is recommended to avoid breastfeeding while on treatment.

What useful links are available on this drug?

  • FDA Approval: https://bit.ly/3amDO1b
  • Prescribing Information: https://bit.ly/3aga8mp

Any ongoing clinical trials related to sirolimus protein-bound particles?

Trials are ongoing for use of sirolimus protein-bound particles in combination with chemotherapy for pediatric patients with recurrent or refractory solid tumors. More information is available about these clinical trials at https://clinicaltrials.gov.

Janelle E. Mann, PHARMD, BCOP, is Clinical Oncology Pharmacist/Manager, Clinical Pharmacy Services at Washington University School of Medicine, St. Louis, Mo. She serves as the Pharmacy Forum column editor. 

Tuesday, June 21, 2022

By Michelle Sproat, PharmD

What is infigratinib?
Infigratinib is an orally bioavailable, selective pan-fibroblast growth factor receptor (FGFR) kinase inhibitor. It works as a tyrosine kinase inhibitor that selectively inhibits FGFR signaling and decreases cell proliferation in cancer cell lines with activating FGFR amplifications, mutations, or fusions.

Infigratinib is currently approved for previously treated, unresectable, locally advanced, or metastatic cholangiocarcinoma in adults with a FGFR2 fusion or other FGFR2 rearrangement (as detected by an FDA-approved test).

Infigratinib was approved under accelerated approval based on results from CBGJ398X2204, an international, open-label, single-arm, multi-cohort, Phase II study (NCT02150967; Lancet Gastroenterol Hepatol 2021;6:803-15). Eligible patients had locally advanced or metastatic cholangiocarcinoma, FGFR genetic alterations, and evidence of disease progression after at least one gemcitabine-based regimen. All patients in the study received 125 mg of oral infigratinib once daily for 21 consecutive days, followed by 7 days off, in 28-day cycles until disease progression or unacceptable toxicity.

Cohort 1 (n=108) of CBGJ398X2204, which is now complete and the basis for the current FDA approval, consisted of only patients with FGFR2 fusions (n=88) or other FGFR2 rearrangements (n=20) who had not previously received selective FGFR inhibitors. At a median follow-up of 10.6 months, the objective response rate (defined as proportion of patients with complete or partial response assessed by blind independent review committee) was 23 percent (95% CI 15.6-32.2) with one complete and 24 partial responses. Median duration of response was 5 months with eight patients maintaining response for 6 months or more, including a median progression-free survival of 7.3 months and median overall survival of 12.2 months at time of data cutoff.

How do you administer this drug? 
Infigratinib is administered orally as 125 mg once daily dose for 21 days, followed by 7 days off, for 28-day cycles. It is available as 100 mg and 25 mg capsules. Capsules should be swallowed whole with a glass of water and taken on an empty stomach at least 1 hour before or 2 hours after a meal at the same time every day. Packaging of infigratinib comes in 21-day blister packs with each carton containing a full 28-day cycle (21 doses of 125 mg provided as 100 mg and 25 mg capsules), with additional 100 mg, 75 mg, and 50 mg cartons available to support dose modifications.

Are there any premedications needed for infigratinib?
No premedication is required for infigratinib, which is currently listed as minimal or low (<30%) emetic potential. 

What are the common side effects associated with infigratinib (> or = 20%)?
The most common adverse reactions (≥20%) reported for infigratinib were:  

  • Dermatologic: alopecia (38%), nail toxicity (57%), palmar-plantar erythrodysesthesia syndrome (21%), xeroderma (23%)
  • Gastrointestinal: Abdominal pain (26%), constipation (30%), decreased appetite (22%), diarrhea (24%), dysgeusia (32%), stomatitis (56%), vomiting (21%), xerostomia (25%)
  • Nervous system: fatigue (44%)
  • Neuromuscular & skeletal: arthralgia (32%)
  • Ophthalmic: abnormal eyelash growth (25%), blurred vision (21%), dry eye syndrome (44%)
  • Lab abnormalities (>20%)

Chemistry: increased creatinine (93%), increased phosphate (90%) decreased phosphate (64%), increased alkaline phosphatase (54%), increased alanine aminotransferase (51%), increased lipase (44%), increased calcium (43%), decreased sodium (41%), increased triglycerides (38%), increased aspartate aminotransferase (38%), increased urate (37%), decreased albumin (24%), increased bilirubin (24%), decreased potassium (21%)
Hematology: decreased hemoglobin (53%), decreased lymphocytes (43%), decreased platelets (37%), decreased leukocytes (26%)

What are the uncommon side effects associated with infigratinib (less than 10%)?
Rare but serious side effects reported with infigratinib include ocular toxicities such as retinal pigment epithelial detachment; fractures; and vascular, cutaneous, and myocardial calcification.

Are there any important drug interactions I should be aware of?
Infigratinib is a major substrate of CYP3A4 and it is recommended to avoid concomitant use of infigratinib with strong or moderate CYP3A inhibitors or inducers. Coadministration of infigratinib with a gastric acid-reducing agent may decrease infigratinib concentrations. Patients on infigratinib should avoid concomitant administration of proton pump inhibitors and, if possible, H2-receptor antagonists (H2RA) and locally acting antacids. If coadministration cannot be avoided, administer infigratinib 2 hours before or 10 hours after H2RA or 2 hours before or 2 hours after locally acting antacids.

How do I adjust the dose in the setting of renal or hepatic insufficiency?

In patients with mild or moderate renal impairment at the start of treatment (CrCl 30-89 mL/minute, estimated by Crockcroft-Gault), the recommendation is to initiate infigratinib at a reduced dose of 100 mg once daily for 21 days of a 28-day cycle. For patients with mild hepatic impairment (total bilirubin 1-1.5 times ULN or AST>ULN), it is recommended to initiate treatment at 100 mg once daily for 21 days (28-day cycle) and moderate hepatic impairment (total bilirubin 1.5-3 times ULN) at 75 mg once daily for 21 days (28-day cycle). Infigratinib has not been studied in patients with severe renal impairment (CrCl <30 mL/minute), end-stage renal disease receiving hemodialysis, or severe hepatic impairment (total bilirubin >3 times ULN) and no recommendations are provided in the package insert.

What should my patients know about infigratinib? 

  • Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception throughout treatment and for at least 1 month after the last dose due to risk of fetal harm.
  • Ocular toxicity may occur while taking infigratinib. Patients should be closely monitored by an ophthalmologist and report any visual changes immediately. Patients should also be advised to use artificial tears or lubricating gel to prevent and/or treat dry eyes.
  • Inform patients that infigratinib may cause hyperphosphatemia. Patients should report any symptoms related to acute changes in phosphate, such as muscle cramps, numbness, or tingling around the mouth.
  • Patients should be informed that infigratinib has significant drug interactions and to inform their health care providers of all concomitant medications and ask before starting any new medication, including over-the-counter and herbal supplements.

What else should I know about infigratinib?

  • Infigratinib was granted accelerated approval based on the overall response rate and duration of response shown in CBGJ398X2204. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
  • Increased phosphate levels occurred in 82 percent of patients with a median onset time of 8 days and phosphate binders being administered to 83 percent of patients who received infigratinib. Phosphate levels should be monitored throughout treatment and phosphate-lowering therapy is recommended to be initiated when phosphate level is >5.5 mg/dL. If serum phosphate is >7.5 mg/dL, infigratinib should be held. Dose reductions or discontinuation may also be warranted based on duration and severity of hyperphosphatemia. 

What useful links are available regarding infigratinib?

  • FDA Accelerated Approval: https://bit.ly/3LRDww3
  • List of Cleared or Approved Companion Diagnostic Devices: https://bit.ly/3z3qMQq
  • Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol 2018; doi:10.1200/JCO.2017.75.5009: https://bit.ly/38pE3aZ

Any ongoing clinical trials related to infigratinib?
Trials are ongoing looking at infigratinib for other conditions, such as urothelial carcinoma, high-grade glioma, and other metastatic solid tumors with FGFR mutations. More information about these clinical trials can be found at https://clinicaltrials.gov.

Michelle Sproat, PharmD, is Clinical Oncology Pharmacist at Washington University School of Medicine, St. Louis, Mo.

Friday, May 20, 2022

By Janelle E. Mann, PharmD, BCOP

What is nivolumab and relatlimab?

Opdualag is a first-in-class, fixed-dose combination of nivolumab, a programmed death receptor-1 (PD-1) blocking antibody, and relatlimab, a novel lymphocyte activation gene-3 (LAG-3) blocking antibody approved for adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.

How does nivolumab and relatlimab work?

Relatlimab is a human IgG4 monoclonal antibody that binds to LAG-3 receptor and blocks the interaction with LAG-3 and its ligands to reduce pathway-mediated immune response inhibition. Nivolumab is a human IgG4 monoclonal antibody that binds to the PD-1 receptor and blocks interaction with its ligands PD-L1 and PD-L2. Combining nivolumab and relatlimab results in increased T-cell activation compared to the activity of either antibody alone.

What is this approved for?

Nivolumab + relatlimab is approved for adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. Nivolumab + relatlimab was reviewed using the FDA's real-time oncology review pilot program, which aims to ensure safe and effective treatments are available to patients as early as possible, as well as FDA's Project Orbis initiative, which enabled concurrent review by the health authorities in Australia, Brazil, and Switzerland, where the application remains under review. Additionally, the application was granted priority review, fast track designation, and orphan drug designation.

What is the basis for this approval?

Nivolumab + relatlimab was approved for unrescetable or metastatic melanoma based on results from the RELATIVITY-047 trial (N Engl J Med 2022;386:24-34). The trial was an international, double-blind, randomized trial of nivolumab and relatlimab as a fixed-dose combination as compared with nivolumab alone given intravenously (IV) every 4 weeks to previously untreated metastatic or unresectable melanoma.

A total of 714 patients were randomly assigned to receive 160 mg of relatlimab and 480 mg of nivolumab in a fixed-dose combination compared to 480 mg nivolumab every 4 weeks. The primary endpoint was progression-free survival (PFS) determined by blinded independent central review. The observed median PFS was 10.1 months with nivolumab and relatlimab as compared with 4.6 months with nivolumab (HR=0.75; 95% CI, 0.62-0.92). PFS at 12 months was 47.7 percent with nivolumab and relatlimab compared with 36 percent with nivolumab. An additional efficacy outcome was overall survival (OS). At final analysis, OS was not statistically significant (HR=0.80; 95% CI, 0.64-1.01) with median OS not reached in nivolumab and relatlimab arm and 34.1 months in the nivolumab arm. Treatment-related adverse events of Grade 3 or 4 occurred in 18.9 percent of patients in the nivolumab and relatlimab group and 9.7 percent in the nivolumab group.

How do you administer this drug?

Nivolumab and relatlimab recommended dose for adult and pediatric patients 12 years of age or older who weigh at least 40 kg is 480 mg nivolumab and 160 mg relatlimab at a fixed-dose combination given IV every 4 weeks. The recommended dose for pediatric patients 12 years of age or older who weigh less than 40 kg has not been established. The infusion is administered over 30 minutes through an IV line containing a 0.2-1.2 micrometer inline filter.

Nivolumab + relatlimab is formulated as a fixed-dose combination manufactured as nivolumab 240 mg and relatlimab 80 mg per 20 mL vial. Based on the FDA-approved dose-infusion centers will require use of two vials to make the appropriate fixed dose of nivolumab 480 mg and relatlimab 160 mg.

Are there any premedications needed?

No premedications are required for nivolumab and relatlimab.

What are the common side effects associated this treatment (> or =10%)?

The following side effects are reported for nivolumab and relatlimab:

  • Gastrointestinal: decreased appetite (15%), diarrhea (</= 24%), nausea (17%)
  • Dermatologic: pruritus (25%), skin rash (9-28%), vitiligo (<15%)
  • Increased lab values: aspartate aminotransferase (AST) (30%), alanine aminotransferase (ALT) (26%), alkaline phosphatase (19%), serum creatinine (19%)
  • Neuromuscular & Skeletal: musculoskeletal pain (45%)
  • Hematologic: lymphocytopenia (32%)
  • Respiratory: cough (15%)
  • Decreased lab values: sodium (24%)
  • Other: fatigue (39%), headache (18%)

What are the uncommon side effects associated with nivolumab and relatlimab (less than 10%)?

Adrenocortical insufficiency, hyperthyroidism, hypophysitis, thyroiditis, colitis, hepatitis, nephritis, pneumonitis, infusion-related reaction, myocarditis, and arthralgia occurred in less than 10 percent of patients on nivolumab and relatlimab.

Are there any important drug interactions I should be aware of?
Nivolumab and relatlimab has no reported drug interactions.

How do I adjust the dose in the setting of renal or hepatic insufficiency?

There are no recommended dose adjustments for renal or hepatic impairment; however, the development of nephritis with kidney dysfunction or hepatotoxicity while on therapy may warrant holding therapy.

What should my patients know about nivolumab and relatlimab?

  • Nivolumab and relatlimab should be used with caution in patients who have underlying autoimmune disorders. Patients should inform their provider of any significant history of treatment for an autoimmune disorder.
  • Immune-mediated toxicities can develop and close monitoring of labs is warranted to catch early signs of liver and renal toxicities. Thyroid function should be monitored at the start of treatment and periodically during treatment to catch changes with thyroid function while on treatment.

What else should I know about nivolumab and relatlimab?

Immune-mediated toxicities can occur while on therapy and warrant early intervention with steroids and holding therapy based on degree of toxicity. Patients should be educated on toxicities such as adrenal insufficiency, hypophysitis, thyroid disorders, diabetes mellitus, diarrhea/colitis, myocarditis, pneumonitis, rash/dermatologic toxicity, neurotoxicity, and ocular disorders.

What useful links are available regarding nivolumab and relatlimab?

  • FDA Approval: https://bit.ly/3vYiyWz
  • Prescribing Information: https://bit.ly/3LIeccD

Any ongoing clinical trials related to nivolumab and relatlimab?

Trials are ongoing for use of nivolumab and relatlimab in metastatic uveal melanoma, and expanded options for several advanced solid tumors. More information is available about these clinical trials at https://clinicaltrials.gov.

Janelle E. Mann, PharmD, BCOP, is Clinical Oncology Pharmacist/Manager, Clinical Pharmacy Services at Washington University School of Medicine, St. Louis, Mo. She serves as the Pharmacy Forum column editor.