REVTORPYK Powder for solution for injection Ref.[116743] Active ingredients: Gedatolisib

5.1 Stomatitis

REVTORPYK can cause severe stomatitis, including ulcers and oral mucositis.

In Study 1 of VIKTORIA-1, stomatitis occurred in 72% of patients treated with REVTORPYK with fulvestrant and palbociclib, including Grade 3 events in 22% of patients. Prophylactic steroid-containing alcohol-free mouthwash was required for a minimum of 8 weeks. The median time to onset was 7 days (range: 1 to 457 days). Stomatitis led to REVTORPYK dose reduction in 19% and permanent discontinuation in 3.8% of patients. Stomatitis occurred in 58% of patients treated with REVTORPYK with fulvestrant, including Grade 3 events in 12% of patients. The median time to onset was 4 days (range: 1 to 524 days). Stomatitis led to REVTORPYK dose reduction in 9% and permanent discontinuation in 1.5% of patients.

Prophylactically initiate steroid-containing alcohol-free mouthwash to reduce the incidence and severity of stomatitis [see Dosage and Administration (2.3)].

If stomatitis occurs, increase the frequency of mouthwash and administer other topical treatments as clinically indicated. Withhold, reduce dose, or permanently discontinue REVTORPYK based on severity [see Dosage and Administration (2.4)].

5.2 Dermatologic Adverse Reactions

REVTORPYK can cause severe rash.

In Study 1 of VIKTORIA-1, rash occurred in 30% of patients treated with REVTORPYK in combination with fulvestrant and palbociclib, including Grade 3 events in 6% of patients. The median time to onset was 21 days (range: 3 to 260 days) after starting REVTORPYK. Rash led to REVTORPYK dose reduction in 5% and permanent discontinuation in 0.8% of patients. Rash occurred in 40% of patients treated with REVTORPYK in combination with fulvestrant, including Grade 3 events in 5% of patients. Rash led to REVTORPYK dose reduction in 6% and permanent discontinuation in 0.8% of patients. The median time to onset was 31.5 days (range: 2 to 407 days) after starting REVTORPYK.

Monitor patients receiving REVTORPYK for rash and infectious sequelae. Instruct patients to limit sun exposure during REVTORPYK treatment.

Withhold, reduce dose, or permanently discontinue REVTORPYK based on severity [see Dosage and Administration (2.4)].

5.3 Hyperglycemia

Severe hyperglycemia can occur in patients treated with REVTORPYK. Hyperglycemia is associated with drugs that inhibit the PI3K/AKT/mTOR pathway.

In Study 1 of VIKTORIA-1, increased fasting glucose (FG) from baseline occurred in 46% of patients treated with REVTORPYK in combination with fulvestrant and palbociclib, including Grade 1 (FG >ULN to 160 mg/dL) in 36% of patients, Grade 2 (FG >160 to 250 mg/dL) in 8% of patients and Grade 3 (FG >250 to 500 mg/dL) in 0.9% of patients. Increased fasting glucose from baseline occurred in 57% of patients treated with REVTORPYK in combination with fulvestrant, including Grade 1 in 44% of patients, Grade 2 in 11% of patients and Grade 3 in 1.8% of patients.

The safety of REVTORPYK in patients with Type 1 or uncontrolled Type 2 diabetes mellitus has not been established as these patients were excluded from Study 1 of VIKTORIA-1 [see Clinical Studies (14)].

Before initiating treatment with REVTORPYK, test fasting glucose levels (FPG or FBG), HbA1c levels, and optimize fasting glucose. Achieve optimal glucose control before starting each REVTORPYK infusion [see Dosage and Administration (2.4)]. Manage hyperglycemia with anti-hyperglycemic medications. Patients with a history of well-controlled Type 2 diabetes mellitus may require intensified anti-hyperglycemic treatment and close monitoring of FG levels. Consider consultation with a healthcare professional experienced in the treatment of hyperglycemia. Initiate at-home glucose monitoring for patients with HbA1c level >6.4%. Advise patients of the signs and symptoms of hyperglycemia and counsel patients on lifestyle changes.

Withhold, reduce dose, or permanently discontinue REVTORPYK based on severity [see Dosage and Administration (2.4)].

5.4 Embryo-Fetal Toxicity

Based on its mechanism of action, REVTORPYK can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Inhibition of PI3K and mTOR pathways have been associated with adverse embryo-fetal growth and lethality in animals.

Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with REVTORPYK and for 2 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with REVTORPYK and for 2 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].

REVTORPYK is used in combination with fulvestrant, with or without palbociclib. Refer to the Prescribing Information of fulvestrant and palbociclib for pregnancy and contraception information. When REVTORPYK is used in combination, advise patients to use effective contraception during treatment and for the longest post-treatment duration recommended in the Prescribing Information of any of the individual products.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Stomatitis [see Warnings and Precautions (5.1)]
• Dermatologic adverse reactions [see Warnings and Precautions (5.2)]
• Hyperglycemia [see Warnings and Precautions (5.3)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of REVTORPYK was evaluated in 383 adult patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer without a detectable PIK3CA mutation in Study 1 of VIKTORIA-1 [see Clinical Studies (14)].

Patients received either Arm A: REVTORPYK 180 mg intravenously once weekly for 3 weeks on followed by 1 week off (Days 1, 8, 15 for each 28-day cycle) in combination with fulvestrant 500 mg intramuscularly on cycle 1 Days 1 and 15, and then at Day 1 of each subsequent 28-day cycle and palbociclib 125 mg orally once daily for 21 days followed by 7 days off treatment for each 28-day cycle (n=130); or Arm B: REVTORPYK in combination with fulvestrant (n=130); or Arm C: fulvestrant alone (n=123). The dose, route of administration, and frequency of each drug in Arms B and C were the same as Arm A. The median duration of exposure for REVTORPYK plus fulvestrant and palbociclib was 6.2 months (range: 0.5 to 25 months) and 5.7 months (range: 0 to 26 months) for REVTORPYK plus fulvestrant.

REVTORPYK in Combination with Fulvestrant and Palbociclib

Serious adverse reactions occurred in 25% of patients who received REVTORPYK in combination with fulvestrant and palbociclib. Serious adverse reactions in ≥1% of patients included pneumonia (3.8%), thrombosis (3.8%), and stomatitis (1.5%). Fatal adverse reactions occurred in 2.3% of patients who received REVTORPYK in combination with fulvestrant and palbociclib, including (0.8% each) pneumonia, multiorgan failure, and hepatic failure.

Permanent discontinuation of REVTORPYK due to an adverse reaction occurred in 12% of patients receiving REVTORPYK in combination with fulvestrant and palbociclib. Adverse reactions that resulted in permanent discontinuation of REVTORPYK were stomatitis, nausea, rash, pneumonitis, diplopia, hypertension, vomiting, breast ulceration, and squamous cell carcinoma of the lung.

Dosage interruptions of REVTORPYK due to an adverse reaction occurred in 64% of patients receiving REVTORPYK in combination with fulvestrant and palbociclib. Adverse reactions which required dosage interruption of REVTORPYK in ≥2% of patients included neutropenia, stomatitis, decreased neutrophil count, fatigue, anemia, leukopenia, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), pyrexia, rash, thrombosis, pneumonia, diarrhea, hyperglycemia, thrombocytopenia, upper respiratory tract infection, pruritus, and urinary tract infection.

Dose reductions of REVTORPYK due to an adverse reaction occurred in 41% of patients receiving REVTORPYK in combination with fulvestrant and palbociclib. Adverse reactions which required dose reduction of REVTORPYK in ≥2% of patients included stomatitis, neutropenia, rash, nausea, increased AST, and increased ALT.

The most common (≥20%) adverse reactions, including laboratory abnormalities, in the REVTORPYK in combination with fulvestrant and palbociclib arm were decreased white blood cell, decreased neutrophils, decreased hemoglobin, decreased lymphocytes, stomatitis, nausea, decreased platelets, increased fasting glucose, fatigue, vomiting, rash, constipation, diarrhea, increased ALT, increased AST, musculoskeletal pain, decreased sodium, and increased eosinophils.

REVTORPYK in Combination with Fulvestrant

Serious adverse reactions occurred in 19% of patients who received REVTORPYK in combination with fulvestrant. Serious adverse reactions in ≥1% of patients included pneumonia (3.8%), thrombosis (2.3%), pleural effusion (1.5%), and pneumonitis (1.5%). Fatal adverse reactions occurred in 2.3% of patients who received REVTORPYK in combination with fulvestrant, including (0.8% each) acute respiratory failure, bronchopulmonary hemorrhage, and cardiac arrest.

Permanent discontinuation of REVTORPYK due to an adverse reaction occurred in 9% of patients receiving REVTORPYK in combination with fulvestrant. Adverse reactions that resulted in permanent discontinuation of REVTORPYK were stomatitis, nausea, rash, pneumonitis, acute respiratory failure, myocarditis, angina pectoris, fatigue, infusion-related reaction, peripheral neuropathy, and oral pain.

Dosage interruptions of REVTORPYK due to an adverse reaction occurred in 37% of patients receiving REVTORPYK in combination with fulvestrant. Adverse reactions which required dosage interruption of REVTORPYK in ≥2% of patients included fatigue, increased AST, increased ALT, stomatitis, pneumonia, pyrexia, and diarrhea.

Dose reductions of REVTORPYK due to an adverse reaction occurred in 22% of patients receiving REVTORPYK in combination with fulvestrant. Adverse reactions which required dose reduction of REVTORPYK in ≥2% of patients included stomatitis, rash, and nausea.

The most common (≥20%) adverse reactions, including laboratory abnormalities, in the REVTORPYK in combination with fulvestrant arm were stomatitis, increased fasting glucose, increased eosinophils, decreased hemoglobin, nausea, rash, increased ALT, fatigue, musculoskeletal pain, decreased lymphocytes, vomiting, increased AST, pruritus, and diarrhea.

Tables 4 and 5 summarize the adverse reactions and laboratory abnormalities in Study 1 of VIKTORIA-1, respectively.

Table 4. Adverse Reactions (≥10%) in Patients Who Received REVTORPYK plus Fulvestrant and Palbociclib in Study 1 of VIKTORIA-1:

Grading according to CTCAE 5.0.
N=number of patients.
^a Includes multiple related terms.
^b No Grade 4 events were reported.

Table 5. Select Laboratory Abnormalities (≥10%) in Patients Who Received REVTORPYK plus Fulvestrant and Palbociclib in Study 1 of VIKTORIA-1:

N = number of patients; WBC = white blood cells; AST = aspartate aminotransferase; ALT = alanine aminotransferase; CPK = creatine phosphokinase; ALP = alkaline phosphatase.
^a Glucose results were graded per CTCAE v4.03.
^b No Grade 4 events were reported.

Risk Summary

REVTORPYK is used in combination with fulvestrant, with or without palbociclib. Refer to the Prescribing Information for fulvestrant and palbociclib for pregnancy information. When used in combination with REVTORPYK, advise patients to use effective contraception during treatment and for the longest post-treatment duration recommended in the Prescribing Information of any of the individual products.

Based on its mechanism of action, REVTORPYK can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug- associated risk. Animal reproductive toxicity studies have not been conducted with REVTORPYK. Inhibition of PI3K and mTOR pathways have been associated with adverse embryo-fetal growth and lethality in animals (see Data).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

PIK3CA knockout mice experienced developmental delay at embryonic day 9.5 and mortality between embryonic day 9.5 and 10.5. mTOR knockout mice experienced early lethality by embryonic day 7.5. In both animal models, early embryonic death was a result of impaired cell proliferation and structural development.

Risk Summary

REVTORPYK is used in combination with fulvestrant, with or without palbociclib. Refer to the Prescribing Information for fulvestrant and palbociclib for lactation information. When used in combination with REVTORPYK, advise patients to not breastfeed during treatment and for the longest post-treatment duration recommended in the Prescribing Information of any of the individual products.

There are no data on the presence of gedatolisib or its metabolites in human milk, its effects on milk production, or a breastfed child. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women to not breastfeed during treatment with REVTORPYK and for 2 weeks after the last dose.

REVTORPYK is used in combination with fulvestrant, with or without palbociclib. Refer to the Prescribing Information for fulvestrant and palbociclib for contraception and infertility information. When used in combination with REVTORPYK, advise patients to use effective contraception during treatment and for the longest post-treatment duration recommended in the Prescribing Information of any of the individual products.

Based on its mechanism of action, REVTORPYK can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating treatment with REVTORPYK.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with REVTORPYK and for 2 weeks after the last dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with REVTORPYK and for 2 weeks after the last dose.

Infertility

Based on animal studies, REVTORPYK may impair fertility in females and males of reproductive potential. Findings in animals were reversible [see Nonclinical Toxicology (13.1)].

The safety and efficacy of REVTORPYK in pediatric patients have not been established.

Of 260 patients who received REVTORPYK, 55 patients (21%) were ≥65 and <75 years of age and 17 patients (6.5%) were ≥75 years of age [see Clinical Studies (14)].

In patients treated with REVTORPYK in combination with fulvestrant and palbociclib, the incidence of Grade ≥3 stomatitis and rash was higher in patients ≥65 years of age (37% and 11%, respectively) compared to younger patients (16% and 4.3%, respectively). In patients treated with REVTORPYK in combination with fulvestrant, the incidence of Grade ≥3 stomatitis and rash was higher in patients ≥65 years of age (18% and 12%, respectively) compared to younger patients (10% and 3.1%, respectively). No overall differences in effectiveness of REVTORPYK were observed between patients ≥65 years of age and younger patients.