KEYTRUDA SSI JULY 24

KEYTRUDA® (pembrolizumab) SELECTED SAFETY INFORMATION SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Immune-mediated Adverse Reactions: Immune-mediated adverse reactions, including severe and fatal cases, have occurred in patients receiving KEYTRUDA. Immune-related adverse reactions have occurred after discontinuation of treatment with KEYTRUDA. Immune-mediated adverse reactions affecting more than one body system can occur simultaneously.

KEYTRUDA® (pembrolizumab) SELECTED SAFETY INFORMATION
SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Immune-mediated Adverse Reactions
Immune-mediated adverse reactions, including severe and fatal cases, have occurred in patients receiving KEYTRUDA. Immune-related adverse reactions have occurred after discontinuation of treatment with KEYTRUDA. Immune-mediated adverse reactions affecting more than one body system can occur simultaneously.

  • Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immunemediated adverse reactions. Monitor patients for changes in thyroid and liver function (hepatic transaminase and bilirubin levels) at the start of treatment, periodically during treatment and as indicated based on clinical evaluation. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm aetiology or exclude other causes. Institute medical management promptly, including specialty consultation as appropriate.
  • No dose reductions of KEYTRUDA are recommended. Withhold or discontinue KEYTRUDA to manage adverse reactions as described in the Product Information. Based on the severity of the adverse reaction, withhold KEYTRUDA and consider administration of corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less following corticosteroid taper. If another episode of a severe adverse reaction occurs, permanently discontinue KEYTRUDA.

Immune-mediated pneumonitis

  • Pneumonitis (including fatal cases) has been reported in patients receiving KEYTRUDA. Pneumonitis (all Grades) occurred in 3.4% of 2799 patients with melanoma or NSCLC receiving KEYTRUDA. Incidences of pneumonitis in individual studies in patients with melanoma and or non-small cell lung cancer treated with KEYTRUDA as monotherapy (n = 2799) ranged from 1.6% to 5.8%. In individual studies of patients with NSCLC treated with KEYTRUDA as monotherapy (n = 2602), the incidence of pneumonitis (all Grades) ranged from 3.8% to 8.3%. In cHL patients treated with KEYTRUDA as monotherapy, the incidence of pneumonitis (all Grades) ranged from 5.2% to 10.8% for cHL patients in KEYNOTE-087 (n = 210) and KEYNOTE-204 (n = 148), respectively.

Immune-mediated colitis

  • Colitis has been reported in patients receiving KEYTRUDA. Colitis (all Grades) occurred in 1.7% of 2799 patients with melanoma or NSCLC receiving KEYTRUDA.
  • The potential risk of gastrointestinal perforation should be taken into consideration.

Immune-mediated hepatitis (KEYTRUDA) and hepatotoxicity (KEYTRUDA in Combination with Axitinib)

Immune-mediated hepatitis

  • Hepatitis has been reported in patients receiving KEYTRUDA. Hepatitis (all Grades) occurred in 0.7% of 2799 patients with melanoma or NSCLC receiving KEYTRUDA.

Hepatotoxicity in Combination with Axitinib

  • KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone.
  • Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib and consider administering corticosteroids as needed.

Immune-mediated nephritis

  • Nephritis has been reported in patients receiving KEYTRUDA. Nephritis (all Grades) occurred in 0.3% of 2799 patients with melanoma or NSCLC receiving KEYTRUDA.
  • Nephritis appears to be more common when KEYTRUDA is used in combination with pemetrexed and platinum chemotherapy than when KEYTRUDA is used alone. In patients with non-squamous NSCLC treated with KEYTRUDA in combination with pemetrexed and platinum chemotherapy (n = 405), the incidence of nephritis was 1.7% (all Grades).

Immune-mediated endocrinopathies

  • Adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders (including hyperthyroidism, hypothyroidism and thyroiditis), and type 1 diabetes mellitus (including diabetic ketoacidosis) have been reported in patients receiving KEYTRUDA.
  • In 2799 patients with melanoma and NSCLC, the following immune-mediated endocrinopathies (all Grades) occurred in patients treated with KEYTRUDA:
    • Adrenal insufficiency occurred in 0.8% of patients
    • Hypophysitis occurred in 0.6% of patients
    • Hypothyroidism occurred in 8.5% of patients. In individual studies of patients with HNSCC treated with KEYTRUDA as monotherapy (n = 909), the incidence of hypothyroidism was 16.1% (all Grades) with 0.3% Grade 3. In patients with HNSCC treated with KEYTRUDA in combination with platinum and 5-FU chemotherapy (n = 276), the incidence of hypothyroidism was 15.2%, all of which were Grade 1 or 2. In patients with cHL (n = 389), the incidence of hypothyroidism was 17%, all of which were Grade 1 or 2. In the adjuvant study of patients with resected RCC treated with KEYTRUDA as monotherapy (n = 488) the incidence of hypothyroidism was 21% with 0.2% Grade 3.
    • Hyperthyroidism (all Grades) occurred in 3.4% of patients. In the adjuvant study of patients with resected RCC treated with KEYTRUDA as monotherapy (n = 488) the incidence of hyperthyroidism was 12% with 0.2% Grade 3.
    • Type 1 diabetes mellitus (all Grades) occurred in 0.2% of patients

Severe skin reactions

Immune-mediated severe skin reactions have been reported in patients treated with KEYTRUDA. Cases of Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN) and bullous pemphigoid, have been reported in patients treated with KEYTRUDA. Some cases of SJS and TEN have had a fatal outcome. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialised care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other immune-mediated adverse reactions

  • The following additional clinically significant, immune-mediated adverse reactions were reported in less than 1% of patients treated with KEYTRUDA in KEYNOTE-001, KEYNOTE-002, KEYNOTE-006, and KEYNOTE- 010: uveitis, myositis, Guillain-Barre syndrome, pancreatitis, encephalitis, sarcoidosis, myasthenic syndrome/myasthenia gravis (including exacerbation), myelitis, vasculitis, hypoparathyroidism, gastritis, and haemolytic anaemia.
  • The following were reported in other clinical studies with KEYTRUDA or in post-marketing use: myocarditis, pericarditis and pericardial effusion, peripheral neuropathy, sclerosing cholangitis, and exocrine pancreatic insufficiency.
  • Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA versus the risk of possible organ rejection in these patients.

Increased mortality in patients with multiple myeloma when KEYTRUDA is added to a thalidomide analogue and dexamethasone

Treatment of patients with multiple myeloma with a PD-1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Infusion-related reactions

Severe infusion reactions, including hypersensitivity and anaphylaxis, have been reported in 6 (0.2%) of 2799 patients receiving KEYTRUDA in KEYNOTE-001, KEYNOTE-002, KEYNOTE-006 and KEYNOTE-010. For severe infusion reactions, stop infusion and permanently discontinue KEYTRUDA. Patients with mild or moderate infusion reaction may continue to receive KEYTRUDA with close monitoring; premedication with antipyretic and antihistamine may be considered.

Patient Alert Card

The prescriber must discuss the risks of KEYTRUDA therapy with the patient. The patient should be provided with the Patient Alert Card.

Effects on Fertility

Fertility studies have not been conducted with KEYTRUDA.

Use in Pregnancy (Category D)

Based on its mechanism of action, KEYTRUDA can cause foetal harm when administered to pregnant women. KEYTRUDA is not recommended during pregnancy unless the clinical benefit outweighs the potential risk to the foetus. Women of childbearing potential should use effective contraception during treatment with KEYTRUDA and for at least 4 months following the last dose of KEYTRUDA.

Use in Lactation

It is unknown whether KEYTRUDA is secreted in human milk. A decision should be made whether to discontinue breast-feeding or to discontinue KEYTRUDA.

Paediatric Use

In KEYNOTE-051, 173 paediatric patients (65 children ages 6 months to less than 12 years and 108 adolescents ages 12 years to 17 years) with advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumours were administered KEYTRUDA 2 mg/kg every 3 weeks. The cHL population (n = 30) included patients 6 to 17 years of age. Patients received KEYTRUDA for a median of 4 doses (range 1–52 doses), with 147 patients (85%) receiving KEYTRUDA for 2 doses or more. The concentrations of KEYTRUDA in paediatric patients were comparable to those observed in adult patients at the same dose regimen of 2 mg/kg every 3 weeks.

The safety profile in these paediatric patients was similar to that seen in adults treated with KEYTRUDA. The most common adverse reactions (reported in ≥20% of paediatric patients) were pyrexia (33%), vomiting (30%), headache (25%), abdominal pain (23%), anaemia (21%) and cough (20%). The majority of adverse reactions reported for monotherapy were of Grades 1 or 2 severity. Eighty (46%) patients had 1 or more Grades 3 to 5 adverse reactions of which 5 (2.9%) patients had 1 or more adverse reactions that resulted in death. No new immune-mediated adverse events causally associated with KEYTRUDA are identified in this population.

Efficacy for paediatric patients with melanoma, relapsed or refractory cHL, PMBCL, MSI-H/dMMR cancers, or TMB-H cancers is extrapolated from the results in the respective adult populations and supported by data from KEYNOTE-051. Efficacy has not been established in other paediatric malignancies.

Effects on ability to drive and use machines

KEYTRUDA may have an influence on the ability to drive and use machines. Fatigue has been reported following administration of KEYTRUDA.

Allogeneic Haematopoietic Stem Cell Transplant (HSCT) after treatment with KEYTRUDA in classical Hodgkin Lymphoma

Immune-mediated complications, including fatal events, occurred in patients who underwent HSCT after being treated with KEYTRUDA. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft versus host disease (GVHD), severe (Grade 3–4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

Allogeneic HSCT prior to treatment with KEYTRUDA

In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after treatment with KEYTRUDA. Consider the benefit of treatment with KEYTRUDA versus the risk of possible GVHD in patients with a history of allogeneic HSCT.

Use of KEYTRUDA in urothelial carcinoma patients who have received prior platinum-containing chemotherapy

Physicians should consider the delayed onset of KEYTRUDA effect before initiating treatment in patients with poorer prognostic features and/or aggressive disease. In urothelial cancer, a higher number of deaths within 2 months was observed in KEYTRUDA compared to chemotherapy. Factors associated with early deaths were fast progressive disease on prior platinum therapy and liver metastases.

Use of KEYTRUDA in combination with chemotherapy for first-line treatment of patients with NSCLC

In general, the frequency of adverse reactions for KEYTRUDA combination therapy is observed to be higher than for KEYTRUDA monotherapy or chemotherapy alone, reflecting the contributions of each of these components (See Adverse Effects). A direct comparison of the safety of KEYTRUDA when used in combination with pemetrexed and platinum chemotherapy to KEYTRUDA monotherapy is not available.

Efficacy and safety data from patients ≥75 years are limited. For patients ≥75 years, KEYTRUDA combination therapy should be used with caution after careful consideration of the potential benefit/risk on an individual basis.

INTERACTIONS WITH OTHER MEDICINES

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. The use of systemic corticosteroids or immunosuppressants before starting KEYTRUDA should be avoided, however, systemic corticosteroids or other immunosuppressants can be used after starting KEYTRUDA to treat immune-mediated adverse reactions.

Corticosteroids can also be used as premedication, when KEYTRUDA is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions.

ADVERSE EFFECTS

Clinical trials experience

  • The safety of KEYTRUDA was evaluated in 2799 patients with unresectable or metastatic melanoma or metastatic NSCLC in controlled and uncontrolled studies. The median treatment duration was 4.2 months (range 1 day to 30.4 months) including 1153 patients treated for greater than or equal to six months and 600 patients treated for greater than or equal to one year.
  • KEYTRUDA was discontinued for treatment-related adverse reactions in 5% of patients. Treatment-related serious adverse events (SAEs) reported up to 90 days after the last dose occurred in 10% of patients receiving KEYTRUDA. Of these treatment-related SAEs, the most common were: pneumonitis, colitis, diarrhoea, and pyrexia. The most common treatment-related adverse reactions (reported in >10% of patients) were: fatigue, pruritus, rash, diarrhoea, and nausea.
  • In Melanoma (KEYNOTE-006) the most common adverse events [all Grades (≥10%) and at a higher incidence than in the Ipilimumab arm (between arm difference of ≥5%)] with KEYTRUDA were: arthralgia (18%), cough (17%), back pain (12%) and vitiligo (11%).
  • In Melanoma (KEYNOTE-002) the most common adverse events [all Grades (≥10%) and at a higher incidence than in the chemotherapy arm (between arm difference of ≥5%)] with KEYTRUDA were: pruritus (25%), arthralgia (15%), abdominal pain (13%), rash (13%) and hyponatremia (11%).
  • In the adjuvant treatment of Resected Melanoma (KEYNOTE-054) adverse events that were reported in at least 5% of patients, and at least 5% more frequently with KEYTRUDA than placebo, were: hypothyroidism (14.7% vs 2.8%), hyperthyroidism (10.4% vs 1.2%) and pruritus (19.4% vs. 11.6%). Discontinuation due to adverse events was 14% with adjuvant KEYTRUDA, most commonly due to pneumonitis, colitis and diarrhoea. Compared to placebo, KEYTRUDA was associated with increases in Grade 3–5 adverse events (31.0% vs. 19.1%) and serious adverse events (25.1% vs. 16.3%). A fatal event of immune-mediated myositis occurred in the KEYTRUDA arm. Among the 969 patients with resected melanoma enrolled in KEYNOTE- 716, the adverse reactions were generally similar to those occurring in patients with unresectable or metastatic melanoma and NSCLC.
  • In NSCLC (KEYNOTE-189) the most common adverse events [all Grades (≥20%) and at a higher incidence than in the placebo with pemetrexed and platinum chemotherapy arm (between arm difference of ≥5%)] with KEYTRUDA in combination with pemetrexed and platinum chemotherapy were: fatigue (41%), diarrhoea (31%), neutropenia (27%), rash (20%) and asthenia (20%). Adverse events occurring in previously untreated patients with NSCLC receiving KEYTRUDA in combination with carboplatin and either paclitaxel or nabpaclitaxel in KEYNOTE-407 were generally similar in KEYNOTE-189 with the exception of alopecia (46%) and arthralgia (21%).
  • In NSCLC (KEYNOTE-042) the most common adverse events [all Grades (≥10%) and at a higher incidence than in the chemotherapy arm (between arm difference of ≥5%)] with KEYTRUDA monotherapy were: dyspnea (17%), cough (16%) and hypothyroidism (12%). Adverse events occurring in previously untreated patients with NSCLC receiving KEYTRUDA in KEYNOTE-024 and previously treated patients in KEYNOTE-010 were generally similar to those occurring in patients in KEYNOTE-042.
  • In the adjuvant treatment of Resected NSCLC (KEYNOTE-091), among the 580 patients treated with KEYTRUDA, the adverse reactions were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as monotherapy with the exception of hypothyroidism (21%) and hyperthyroidism (11%).
  • In HNSCC (KEYNOTE-048) the most common adverse reactions [all Grades (≥20%)] in those receiving KEYTRUDA monotherapy were: fatigue (33%), constipation (20%) and rash (20%). KEYTRUDA was discontinued for adverse reactions in 12% of patients in the KEYTRUDA single agent arm. The most common resulting in permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%).
  • In HNSCC (KEYNOTE-048) the most common adverse reactions [all Grades (≥20%)] in those receiving combination treatment with platinum and FU chemotherapy were: nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhoea (29%), decreased appetite (29%), stomatitis (26%) and cough (22%). KEYTRUDA was discontinued for adverse reactions in 16% of patients in the combination arm. The most common resulting in permanent discontinuation were: pneumonia (2.5%), pneumonitis (1.8%) and septic shock (1.4%).
  • In cHL (KEYNOTE⁠-⁠087) KEYTRUDA was discontinued due to adverse reactions in 5% patients. Serious adverse reactions occurred in 16% of patients; those ≥1% included pneumonia, pneumonitis, pyrexia, dyspnoea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhoea (20%), and rash (20%). Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), and myelitis and myocarditis (0.5% each).
  • In cHL (KEYNOTE⁠-⁠204) KEYTRUDA was discontinued due to adverse reactions in 14% of patients. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1% were pneumonia, pneumonitis, interstitial lung disease, pyrexia, myocarditis, acute kidney injury and febrile neutropenia. Three patients died from causes other than disease progression; one from pneumonia, one from hypovolemic shock, and one due to unknown cause. The most common adverse reactions (≥20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhoea (22%), and pyrexia, fatigue, rash, and cough (20% each).
  • In PMBCL (KEYNOTE-170) a higher incidence of pyrexia (28%) possibly due to B-symptoms, and neutropenia (26%) have been noted. The incidence of Grade 3 or 4 neutropenia was 17%, and febrile neutropenia was 2%. Other adverse events were generally similar to those occurring in patients with melanoma or NSCLC.
  • In Urothelial Carcinoma (KEYNOTE-052) the most common adverse reactions (≥20%) were: fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%) and diarrhoea (20%). KEYTRUDA was discontinued due to adverse reactions in 11% of patients. Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia which led to death. Serious adverse reactions occurred in 42% of patients. The most frequent serious adverse reactions (≥2%) were: urinary tract infection, haematuria, acute kidney injury, pneumonia, and urosepsis.
  • In Urothelial Carcinoma (KEYNOTE-045) the most common adverse reactions [all Grades (≥20%)] were: fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%) and rash (20%). KEYTRUDA was discontinued due to adverse reactions in 8% of patients. The most common resulting in permanent discontinuation was pneumonitis (1.9%).
  • In NMIBC (KEYNOTE-057) the most common adverse reactions [all Grades (≥10%)] were: fatigue (29%), diarrhoea (24%), rash (24%), pruritus (20%), musculoskeletal pain (20%), haematuria (19%), cough (19%), arthralgia (14%), nausea (13%), constipation (12%), urinary tract infection (12%), peripheral oedema (11%), hypothyroidism (11%) and nasopharyngitis (10%). KEYTRUDA was discontinued due to adverse reactions in 10% of patients. The most common adverse (1%) reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 27% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (≥2%) in KEYTRUDA-treated patients were: pneumonia (3%), colitis (2%), pulmonary embolism (2%) and urinary tract infection (2%).
  • In MSI-H/dMMR cancer the adverse events were generally similar to those occurring in patients with melanoma or NSCLC.
  • In Endometrial Carcinoma (KEYNOTE-775) the most common adverse reactions [all Grades (≥20%)] with KEYTRUDA in combination with lenvatinib were: hypothyroidism (67%), hypertension (67%), fatigue (58%), diarrhoea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), abdominal pain (34%), weight loss (34%), urinary tract infection (31%), proteinuria (29%), constipation (27%), headache (26%), haemorrhagic events (25%), palmar-plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%). Fatal adverse reactions occurred in 4.7% of those treated with KEYTRUDA and lenvatinib, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal haemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction. Serious adverse reactions occurred in 50% of these patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions ≥3% were: hypertension (4.4%) and urinary tract infections (3.2%). Discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of these patients. The most common adverse reaction leading to discontinuation of KEYTRUDA (≥1%) was increased ALT (1.2%).
  • In Cervical Cancer (KEYNOTE-826) the most common adverse reactions [all Grades (≥20%)] for those receiving KEYTRUDA, chemotherapy with or without bevacizumab were: peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhoea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension (24%), urinary tract infection (24%), and rash (22%). KEYTRUDA was discontinued due to adverse reactions in 15% of patients. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA plus chemotherapy, with or without bevacizumab. The most frequently occurring serious adverse reactions (≥3%) included febrile neutropenia, urinary tract infection, anaemia, acute kidney injury and sepsis. Fatal adverse reactions were reported in 4.6% of patients receiving KEYTRUDA plus chemotherapy, with or without bevacizumab, including 3 cases of haemorrhage, 2 cases of sepsis, 2 cases due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection.
  • In RCC in Combination with axitinib (KEYNOTE-426) the most common adverse reactions [all Grades (≥20%)] with KEYTRUDA in combination with axitinib were: diarrhoea (56%), fatigue/asthenia (52%), hypertension (48%), hypothyroidism (35%), decreased appetite (30%), hepatotoxicity (39%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%) and constipation (21%). Incidences of Grades 3–5 adverse reactions were 76% for KEYTRUDA combination therapy and 71% for sunitinib alone.
  • In the adjuvant treatment of Resected RCC (KEYNOTE-564), when KEYTRUDA was administered as monotherapy, adverse events were generally similar to those occurring in patients with melanoma or NSCLC.
  • In RCC in combination with lenvatinib (KEYNOTE-581) the most common adverse events [all Grades (≥20%) and at a higher incidence than in the sunitinib arm (between arm difference of ≥5%)] with KEYTRUDA in combination with lenvatinib were: diarrhoea (61%), hypertension (55%), hypothyroidism (47%), decreased appetite (40%), nausea (36%), dysphonia (30%), decreased weight (30%), proteinuria (30%), arthralgia (28%), rash (27%), vomiting (26%), constipation (25%), headache (23%), and abdominal pain (21%).
  • In Recurrent or Metastatic cSCC or LA cSCC, adverse events were generally similar to those occurring in patients with melanoma or NSCLC.
  • In Oesophageal Cancer (KEYNOTE-590) adverse reactions occurring in at least 20% of patients and at a higher incidence (≥2%) of Grades 3–5 severity for KEYTRUDA in combination with chemotherapy (cisplatin and 5-FU) compared to placebo and chemotherapy (cisplatin and 5-FU) were: vomiting (7% vs 5%), stomatitis (6% vs 3.8%), neutrophil count decreased (24.1% vs 17.3%), and white blood cell count decreased (9.2% vs 4.9%).
  • In TMB-H Cancer (KEYNOTE-158) adverse reactions were similar to those occurring in patients with other solid tumours who received KEYTRUDA as a single agent.
  • In High-Risk Early-Stage TNBC (KEYNOTE-522), the most common adverse events [all Grades (≥20%)] for those receiving KEYTRUDA in combination with chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide), given as a neoadjuvant treatment followed by surgery then continued alone as adjuvant treatment, were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), peripheral neuropathy (41%), diarrhoea (41%), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%).
  • In Locally Recurrent Unresectable or Metastatic TNBC (KEYNOTE-355), the most common adverse events [all Grades (≥20%)] for those receiving KEYTRUDA in combination with chemotherapy (paclitaxel, nab-paclitaxel, or gemcitabine and carboplatin), were fatigue (48%), nausea (44%), alopecia (34%), diarrhoea (28%), constipation (28%), vomiting (26%), rash (26%), cough (23%), decreased appetite (21%), and headache (20%).

Geriatric Patients

No overall differences in safety or efficacy were reported between elderly patients (65 years and over) and younger patients (less than 65 years). No dose adjustment is necessary in this population.

For combination therapy with KEYTRUDA and axitinib in patients with advanced RCC, limited safety data is available regarding patients ≥75 years of age.

Renal Insufficiency

No dose adjustment is needed for patients with mild or moderate renal impairment. KEYTRUDA has not been studied in patients with severe renal impairment.

Hepatic Insufficiency

No dose adjustment is needed for patients with mild hepatic impairment. KEYTRUDA has not been studied in patients with moderate or severe hepatic impairment.

INDICATIONS

▼This medicinal product is subject to additional monitoring in Australia due to provisional approval of an extension of indication. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse events at www.tga.gov.au/reporting-problems.

Melanoma

KEYTRUDA is indicated as monotherapy for the treatment of unresectable or metastatic melanoma in adults.

KEYTRUDA is indicated for the adjuvant treatment of adult and adolescent (12 years and older) patients with Stage IIB, IIC, or III melanoma who have undergone complete resection.

Non-small Cell Lung Cancer (NSCLC)

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic non-squamous NSCLC, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumour aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA is indicated as monotherapy for the first-line treatment of patients with NSCLC expressing programmed death receptor-ligand 1 (PD-L1) [tumour proportion score (TPS) ≥1%] as determined by a validated test, with no EGFR or ALK genomic tumour aberrations, and is:

  • Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or –
  • Metastatic

KEYTRUDA is indicated as monotherapy for the treatment of patients with advanced NSCLC whose tumours express PD-L1 with a ≥1% TPS as determined by a validated test and who have received platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumour aberrations should have received prior therapy for these aberrations prior to receiving KEYTRUDA.

KEYTRUDA is indicated as monotherapy for the adjuvant treatment of patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC who have undergone complete resection and platinum-based chemotherapy.

Head and Neck Squamous Cell Cancer (HNSCC)

KEYTRUDA, as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, is indicated for the first-line treatment of patients with metastatic or unresectable recurrent HNSCC, and whose tumours express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by a validated test.

KEYTRUDA is indicated as monotherapy for the treatment of patients with metastatic or unresectable recurrent HNSCC with disease progression on or after platinum-containing chemotherapy and whose tumours express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by a validated test.

Classical Hodgkin Lymphoma (cHL)

KEYTRUDA is indicated as monotherapy for the treatment of adult and paediatric patients with relapsed or refractory cHL:

1. Following autologous stem cell transplant (ASCT) or

2. Following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option.

The approval of this indication in paediatric patients is on the basis of objective response rate from patients aged 11 years and older from single arm trial data and extrapolation from adult data.

Primary Mediastinal B-Cell Lymphoma (PMBCL)

KEYTRUDA is indicated for the treatment of adult and paediatric patients with refractory primary PMBCL, or who have relapsed after 2 or more prior lines of therapy. The approval of this indication is on the basis of objective response rate (ORR) and duration of response from non-randomised studies.

Urothelial Carcinoma

KEYTRUDA is indicated as monotherapy for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for any platinum-containing chemotherapy. This indication is approved based on overall response rate and duration of response in a single-arm study. Improvements in overall survival, progression-free survival, or health-related quality of life have not been established.

KEYTRUDA is indicated as monotherapy for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have received platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, highrisk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in-situ (CIS) with or without papillary tumours who are ineligible for or have elected not to undergo cystectomy. This indication was approved via the provisional approval pathway based on complete response rate and duration of response. Continued approval of this indication depends on verification and description of benefit in confirmatory trials.

Microsatellite Instability High (MSI-H) or Mismatch Repair Deficient (dMMR) Cancer

KEYTRUDA is indicated for the treatment of adult and paediatric patients with unresectable or metastatic solid tumours that are MSI-H or dMMR, as determined by a validated test, that have progressed following prior treatment and when there are no satisfactory alternative treatment options.
Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Colorectal Cancer KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic colorectal cancer (CRC) that is MSI-H or dMMR as determined by a validated test.

Endometrial Carcinoma

KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Cervical Cancer

KEYTRUDA, in combination with platinum chemotherapy and paclitaxel, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumours express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by a validated test.

Renal Cell Carcinoma (RCC)

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced RCC.

KEYTRUDA, in combination with lenvatinib, is indicated for the first-line treatment of adult patients with advanced RCC.

KEYTRUDA, as monotherapy, is indicated for the adjuvant treatment of patients with RCC with a clear cell component who are at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

Cutaneous Squamous Cell Carcinoma (cSCC)

KEYTRUDA is indicated as monotherapy for the treatment of adult patients with recurrent or metastatic cSCC or locally advanced cSCC that is not curable by surgery or radiation. This indication was approved via the provisional approval pathway based on objective response rate and duration of response from a single-arm study. Improvements in overall survival, progression-free survival, or health-related quality of life have not been established. Full registration for this indication depends on submission of further clinical data to confirm the clinical benefit of the medicine.

Oesophageal Cancer

KEYTRUDA, in combination with platinum and fluoropyrimidine based chemotherapy, is indicated for the firstline treatment of patients with locally advanced or metastatic carcinoma of the oesophagus or HER2 negative gastroesophageal junction adenocarcinoma (tumour centre 1 to 5 centimetres above the gastroesophageal junction) that is not amenable to surgical resection or definitive chemoradiation.

Tumour Mutational Burden-High (TMB-H) Cancer

KEYTRUDA is indicated for the treatment of adult and paediatric patients with unresectable or metastatic tumour mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumours, as determined by a validated test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication was approved via the provisional approval pathway, based on the pooling of data on objective response rate and response duration across multiple different tissue types in a single-arm trial. The assumption that TMB-H status is predictive of the treatment effect of KEYTRUDA for every tissue type has not been verified. Full registration for this indication depends on verification and description of clinical benefit in confirmatory trials.

Triple-Negative Breast Cancer (TNBC)

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumours express PD-L1 (CPS ≥10) as determined by a validated test and who have not received prior chemotherapy for metastatic disease.

CONTRAINDICATIONS

None.

AU-KEY-01486 v2.0. Issued July 2024.

KEYTRUDA® (pembrolizumab) SELECTED SAFETY INFORMATION
SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Immune-mediated Adverse Reactions
Immune-mediated adverse reactions, including severe and fatal cases, have occurred in patients receiving KEYTRUDA. Immune-related adverse reactions have occurred after discontinuation of treatment with KEYTRUDA. Immune-mediated adverse reactions affecting more than one body system can occur simultaneously.

  • Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immunemediated adverse reactions. Monitor patients for changes in thyroid and liver function (hepatic transaminase and bilirubin levels) at the start of treatment, periodically during treatment and as indicated based on clinical evaluation. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm aetiology or exclude other causes. Institute medical management promptly, including specialty consultation as appropriate.
  • No dose reductions of KEYTRUDA are recommended. Withhold or discontinue KEYTRUDA to manage adverse reactions as described in the Product Information. Based on the severity of the adverse reaction, withhold KEYTRUDA and consider administration of corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less following corticosteroid taper. If another episode of a severe adverse reaction occurs, permanently discontinue KEYTRUDA.

Immune-mediated pneumonitis

  • Pneumonitis (including fatal cases) has been reported in patients receiving KEYTRUDA. Pneumonitis (all Grades) occurred in 3.4% of 2799 patients with melanoma or NSCLC receiving KEYTRUDA. Incidences of pneumonitis in individual studies in patients with melanoma and or non-small cell lung cancer treated with KEYTRUDA as monotherapy (n = 2799) ranged from 1.6% to 5.8%. In individual studies of patients with NSCLC treated with KEYTRUDA as monotherapy (n = 2602), the incidence of pneumonitis (all Grades) ranged from 3.8% to 8.3%. In cHL patients treated with KEYTRUDA as monotherapy, the incidence of pneumonitis (all Grades) ranged from 5.2% to 10.8% for cHL patients in KEYNOTE-087 (n = 210) and KEYNOTE-204 (n = 148), respectively.

Immune-mediated colitis

  • Colitis has been reported in patients receiving KEYTRUDA. Colitis (all Grades) occurred in 1.7% of 2799 patients with melanoma or NSCLC receiving KEYTRUDA.
  • The potential risk of gastrointestinal perforation should be taken into consideration.

Immune-mediated hepatitis (KEYTRUDA) and hepatotoxicity (KEYTRUDA in Combination with Axitinib)

Immune-mediated hepatitis

  • Hepatitis has been reported in patients receiving KEYTRUDA. Hepatitis (all Grades) occurred in 0.7% of 2799 patients with melanoma or NSCLC receiving KEYTRUDA.

Hepatotoxicity in Combination with Axitinib

  • KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone.
  • Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib and consider administering corticosteroids as needed.

Immune-mediated nephritis

  • Nephritis has been reported in patients receiving KEYTRUDA. Nephritis (all Grades) occurred in 0.3% of 2799 patients with melanoma or NSCLC receiving KEYTRUDA.
  • Nephritis appears to be more common when KEYTRUDA is used in combination with pemetrexed and platinum chemotherapy than when KEYTRUDA is used alone. In patients with non-squamous NSCLC treated with KEYTRUDA in combination with pemetrexed and platinum chemotherapy (n = 405), the incidence of nephritis was 1.7% (all Grades).

Immune-mediated endocrinopathies

  • Adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders (including hyperthyroidism, hypothyroidism and thyroiditis), and type 1 diabetes mellitus (including diabetic ketoacidosis) have been reported in patients receiving KEYTRUDA.
  • In 2799 patients with melanoma and NSCLC, the following immune-mediated endocrinopathies (all Grades) occurred in patients treated with KEYTRUDA:
    • Adrenal insufficiency occurred in 0.8% of patients
    • Hypophysitis occurred in 0.6% of patients
    • Hypothyroidism occurred in 8.5% of patients. In individual studies of patients with HNSCC treated with KEYTRUDA as monotherapy (n = 909), the incidence of hypothyroidism was 16.1% (all Grades) with 0.3% Grade 3. In patients with HNSCC treated with KEYTRUDA in combination with platinum and 5-FU chemotherapy (n = 276), the incidence of hypothyroidism was 15.2%, all of which were Grade 1 or 2. In patients with cHL (n = 389), the incidence of hypothyroidism was 17%, all of which were Grade 1 or 2. In the adjuvant study of patients with resected RCC treated with KEYTRUDA as monotherapy (n = 488) the incidence of hypothyroidism was 21% with 0.2% Grade 3.
    • Hyperthyroidism (all Grades) occurred in 3.4% of patients. In the adjuvant study of patients with resected RCC treated with KEYTRUDA as monotherapy (n = 488) the incidence of hyperthyroidism was 12% with 0.2% Grade 3.
    • Type 1 diabetes mellitus (all Grades) occurred in 0.2% of patients

Severe skin reactions

Immune-mediated severe skin reactions have been reported in patients treated with KEYTRUDA. Cases of Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN) and bullous pemphigoid, have been reported in patients treated with KEYTRUDA. Some cases of SJS and TEN have had a fatal outcome. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialised care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other immune-mediated adverse reactions

  • The following additional clinically significant, immune-mediated adverse reactions were reported in less than 1% of patients treated with KEYTRUDA in KEYNOTE-001, KEYNOTE-002, KEYNOTE-006, and KEYNOTE- 010: uveitis, myositis, Guillain-Barre syndrome, pancreatitis, encephalitis, sarcoidosis, myasthenic syndrome/myasthenia gravis (including exacerbation), myelitis, vasculitis, hypoparathyroidism, gastritis, and haemolytic anaemia.
  • The following were reported in other clinical studies with KEYTRUDA or in post-marketing use: myocarditis, pericarditis and pericardial effusion, peripheral neuropathy, sclerosing cholangitis, and exocrine pancreatic insufficiency.
  • Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA versus the risk of possible organ rejection in these patients.

Increased mortality in patients with multiple myeloma when KEYTRUDA is added to a thalidomide analogue and dexamethasone

Treatment of patients with multiple myeloma with a PD-1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Infusion-related reactions

Severe infusion reactions, including hypersensitivity and anaphylaxis, have been reported in 6 (0.2%) of 2799 patients receiving KEYTRUDA in KEYNOTE-001, KEYNOTE-002, KEYNOTE-006 and KEYNOTE-010. For severe infusion reactions, stop infusion and permanently discontinue KEYTRUDA. Patients with mild or moderate infusion reaction may continue to receive KEYTRUDA with close monitoring; premedication with antipyretic and antihistamine may be considered.

Patient Alert Card

The prescriber must discuss the risks of KEYTRUDA therapy with the patient. The patient should be provided with the Patient Alert Card.

Effects on Fertility

Fertility studies have not been conducted with KEYTRUDA.

Use in Pregnancy (Category D)

Based on its mechanism of action, KEYTRUDA can cause foetal harm when administered to pregnant women. KEYTRUDA is not recommended during pregnancy unless the clinical benefit outweighs the potential risk to the foetus. Women of childbearing potential should use effective contraception during treatment with KEYTRUDA and for at least 4 months following the last dose of KEYTRUDA.

Use in Lactation

It is unknown whether KEYTRUDA is secreted in human milk. A decision should be made whether to discontinue breast-feeding or to discontinue KEYTRUDA.

Paediatric Use

In KEYNOTE-051, 173 paediatric patients (65 children ages 6 months to less than 12 years and 108 adolescents ages 12 years to 17 years) with advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumours were administered KEYTRUDA 2 mg/kg every 3 weeks. The cHL population (n = 30) included patients 6 to 17 years of age. Patients received KEYTRUDA for a median of 4 doses (range 1–52 doses), with 147 patients (85%) receiving KEYTRUDA for 2 doses or more. The concentrations of KEYTRUDA in paediatric patients were comparable to those observed in adult patients at the same dose regimen of 2 mg/kg every 3 weeks.

The safety profile in these paediatric patients was similar to that seen in adults treated with KEYTRUDA. The most common adverse reactions (reported in ≥20% of paediatric patients) were pyrexia (33%), vomiting (30%), headache (25%), abdominal pain (23%), anaemia (21%) and cough (20%). The majority of adverse reactions reported for monotherapy were of Grades 1 or 2 severity. Eighty (46%) patients had 1 or more Grades 3 to 5 adverse reactions of which 5 (2.9%) patients had 1 or more adverse reactions that resulted in death. No new immune-mediated adverse events causally associated with KEYTRUDA are identified in this population.

Efficacy for paediatric patients with melanoma, relapsed or refractory cHL, PMBCL, MSI-H/dMMR cancers, or TMB-H cancers is extrapolated from the results in the respective adult populations and supported by data from KEYNOTE-051. Efficacy has not been established in other paediatric malignancies.

Effects on ability to drive and use machines

KEYTRUDA may have an influence on the ability to drive and use machines. Fatigue has been reported following administration of KEYTRUDA.

Allogeneic Haematopoietic Stem Cell Transplant (HSCT) after treatment with KEYTRUDA in classical Hodgkin Lymphoma

Immune-mediated complications, including fatal events, occurred in patients who underwent HSCT after being treated with KEYTRUDA. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft versus host disease (GVHD), severe (Grade 3–4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

Allogeneic HSCT prior to treatment with KEYTRUDA

In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after treatment with KEYTRUDA. Consider the benefit of treatment with KEYTRUDA versus the risk of possible GVHD in patients with a history of allogeneic HSCT.

Use of KEYTRUDA in urothelial carcinoma patients who have received prior platinum-containing chemotherapy

Physicians should consider the delayed onset of KEYTRUDA effect before initiating treatment in patients with poorer prognostic features and/or aggressive disease. In urothelial cancer, a higher number of deaths within 2 months was observed in KEYTRUDA compared to chemotherapy. Factors associated with early deaths were fast progressive disease on prior platinum therapy and liver metastases.

Use of KEYTRUDA in combination with chemotherapy for first-line treatment of patients with NSCLC

In general, the frequency of adverse reactions for KEYTRUDA combination therapy is observed to be higher than for KEYTRUDA monotherapy or chemotherapy alone, reflecting the contributions of each of these components (See Adverse Effects). A direct comparison of the safety of KEYTRUDA when used in combination with pemetrexed and platinum chemotherapy to KEYTRUDA monotherapy is not available.

Efficacy and safety data from patients ≥75 years are limited. For patients ≥75 years, KEYTRUDA combination therapy should be used with caution after careful consideration of the potential benefit/risk on an individual basis.

INTERACTIONS WITH OTHER MEDICINES

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. The use of systemic corticosteroids or immunosuppressants before starting KEYTRUDA should be avoided, however, systemic corticosteroids or other immunosuppressants can be used after starting KEYTRUDA to treat immune-mediated adverse reactions.

Corticosteroids can also be used as premedication, when KEYTRUDA is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions.

ADVERSE EFFECTS

Clinical trials experience

  • The safety of KEYTRUDA was evaluated in 2799 patients with unresectable or metastatic melanoma or metastatic NSCLC in controlled and uncontrolled studies. The median treatment duration was 4.2 months (range 1 day to 30.4 months) including 1153 patients treated for greater than or equal to six months and 600 patients treated for greater than or equal to one year.
  • KEYTRUDA was discontinued for treatment-related adverse reactions in 5% of patients. Treatment-related serious adverse events (SAEs) reported up to 90 days after the last dose occurred in 10% of patients receiving KEYTRUDA. Of these treatment-related SAEs, the most common were: pneumonitis, colitis, diarrhoea, and pyrexia. The most common treatment-related adverse reactions (reported in >10% of patients) were: fatigue, pruritus, rash, diarrhoea, and nausea.
  • In Melanoma (KEYNOTE-006) the most common adverse events [all Grades (≥10%) and at a higher incidence than in the Ipilimumab arm (between arm difference of ≥5%)] with KEYTRUDA were: arthralgia (18%), cough (17%), back pain (12%) and vitiligo (11%).
  • In Melanoma (KEYNOTE-002) the most common adverse events [all Grades (≥10%) and at a higher incidence than in the chemotherapy arm (between arm difference of ≥5%)] with KEYTRUDA were: pruritus (25%), arthralgia (15%), abdominal pain (13%), rash (13%) and hyponatremia (11%).
  • In the adjuvant treatment of Resected Melanoma (KEYNOTE-054) adverse events that were reported in at least 5% of patients, and at least 5% more frequently with KEYTRUDA than placebo, were: hypothyroidism (14.7% vs 2.8%), hyperthyroidism (10.4% vs 1.2%) and pruritus (19.4% vs. 11.6%). Discontinuation due to adverse events was 14% with adjuvant KEYTRUDA, most commonly due to pneumonitis, colitis and diarrhoea. Compared to placebo, KEYTRUDA was associated with increases in Grade 3–5 adverse events (31.0% vs. 19.1%) and serious adverse events (25.1% vs. 16.3%). A fatal event of immune-mediated myositis occurred in the KEYTRUDA arm. Among the 969 patients with resected melanoma enrolled in KEYNOTE- 716, the adverse reactions were generally similar to those occurring in patients with unresectable or metastatic melanoma and NSCLC.
  • In NSCLC (KEYNOTE-189) the most common adverse events [all Grades (≥20%) and at a higher incidence than in the placebo with pemetrexed and platinum chemotherapy arm (between arm difference of ≥5%)] with KEYTRUDA in combination with pemetrexed and platinum chemotherapy were: fatigue (41%), diarrhoea (31%), neutropenia (27%), rash (20%) and asthenia (20%). Adverse events occurring in previously untreated patients with NSCLC receiving KEYTRUDA in combination with carboplatin and either paclitaxel or nabpaclitaxel in KEYNOTE-407 were generally similar in KEYNOTE-189 with the exception of alopecia (46%) and arthralgia (21%).
  • In NSCLC (KEYNOTE-042) the most common adverse events [all Grades (≥10%) and at a higher incidence than in the chemotherapy arm (between arm difference of ≥5%)] with KEYTRUDA monotherapy were: dyspnea (17%), cough (16%) and hypothyroidism (12%). Adverse events occurring in previously untreated patients with NSCLC receiving KEYTRUDA in KEYNOTE-024 and previously treated patients in KEYNOTE-010 were generally similar to those occurring in patients in KEYNOTE-042.
  • In the adjuvant treatment of Resected NSCLC (KEYNOTE-091), among the 580 patients treated with KEYTRUDA, the adverse reactions were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as monotherapy with the exception of hypothyroidism (21%) and hyperthyroidism (11%).
  • In HNSCC (KEYNOTE-048) the most common adverse reactions [all Grades (≥20%)] in those receiving KEYTRUDA monotherapy were: fatigue (33%), constipation (20%) and rash (20%). KEYTRUDA was discontinued for adverse reactions in 12% of patients in the KEYTRUDA single agent arm. The most common resulting in permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%).
  • In HNSCC (KEYNOTE-048) the most common adverse reactions [all Grades (≥20%)] in those receiving combination treatment with platinum and FU chemotherapy were: nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhoea (29%), decreased appetite (29%), stomatitis (26%) and cough (22%). KEYTRUDA was discontinued for adverse reactions in 16% of patients in the combination arm. The most common resulting in permanent discontinuation were: pneumonia (2.5%), pneumonitis (1.8%) and septic shock (1.4%).
  • In cHL (KEYNOTE⁠-⁠087) KEYTRUDA was discontinued due to adverse reactions in 5% patients. Serious adverse reactions occurred in 16% of patients; those ≥1% included pneumonia, pneumonitis, pyrexia, dyspnoea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhoea (20%), and rash (20%). Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), and myelitis and myocarditis (0.5% each).
  • In cHL (KEYNOTE⁠-⁠204) KEYTRUDA was discontinued due to adverse reactions in 14% of patients. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1% were pneumonia, pneumonitis, interstitial lung disease, pyrexia, myocarditis, acute kidney injury and febrile neutropenia. Three patients died from causes other than disease progression; one from pneumonia, one from hypovolemic shock, and one due to unknown cause. The most common adverse reactions (≥20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhoea (22%), and pyrexia, fatigue, rash, and cough (20% each).
  • In PMBCL (KEYNOTE-170) a higher incidence of pyrexia (28%) possibly due to B-symptoms, and neutropenia (26%) have been noted. The incidence of Grade 3 or 4 neutropenia was 17%, and febrile neutropenia was 2%. Other adverse events were generally similar to those occurring in patients with melanoma or NSCLC.
  • In Urothelial Carcinoma (KEYNOTE-052) the most common adverse reactions (≥20%) were: fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%) and diarrhoea (20%). KEYTRUDA was discontinued due to adverse reactions in 11% of patients. Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia which led to death. Serious adverse reactions occurred in 42% of patients. The most frequent serious adverse reactions (≥2%) were: urinary tract infection, haematuria, acute kidney injury, pneumonia, and urosepsis.
  • In Urothelial Carcinoma (KEYNOTE-045) the most common adverse reactions [all Grades (≥20%)] were: fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%) and rash (20%). KEYTRUDA was discontinued due to adverse reactions in 8% of patients. The most common resulting in permanent discontinuation was pneumonitis (1.9%).
  • In NMIBC (KEYNOTE-057) the most common adverse reactions [all Grades (≥10%)] were: fatigue (29%), diarrhoea (24%), rash (24%), pruritus (20%), musculoskeletal pain (20%), haematuria (19%), cough (19%), arthralgia (14%), nausea (13%), constipation (12%), urinary tract infection (12%), peripheral oedema (11%), hypothyroidism (11%) and nasopharyngitis (10%). KEYTRUDA was discontinued due to adverse reactions in 10% of patients. The most common adverse (1%) reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 27% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (≥2%) in KEYTRUDA-treated patients were: pneumonia (3%), colitis (2%), pulmonary embolism (2%) and urinary tract infection (2%).
  • In MSI-H/dMMR cancer the adverse events were generally similar to those occurring in patients with melanoma or NSCLC.
  • In Endometrial Carcinoma (KEYNOTE-775) the most common adverse reactions [all Grades (≥20%)] with KEYTRUDA in combination with lenvatinib were: hypothyroidism (67%), hypertension (67%), fatigue (58%), diarrhoea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), abdominal pain (34%), weight loss (34%), urinary tract infection (31%), proteinuria (29%), constipation (27%), headache (26%), haemorrhagic events (25%), palmar-plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%). Fatal adverse reactions occurred in 4.7% of those treated with KEYTRUDA and lenvatinib, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal haemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction. Serious adverse reactions occurred in 50% of these patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions ≥3% were: hypertension (4.4%) and urinary tract infections (3.2%). Discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of these patients. The most common adverse reaction leading to discontinuation of KEYTRUDA (≥1%) was increased ALT (1.2%).
  • In Cervical Cancer (KEYNOTE-826) the most common adverse reactions [all Grades (≥20%)] for those receiving KEYTRUDA, chemotherapy with or without bevacizumab were: peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhoea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension (24%), urinary tract infection (24%), and rash (22%). KEYTRUDA was discontinued due to adverse reactions in 15% of patients. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA plus chemotherapy, with or without bevacizumab. The most frequently occurring serious adverse reactions (≥3%) included febrile neutropenia, urinary tract infection, anaemia, acute kidney injury and sepsis. Fatal adverse reactions were reported in 4.6% of patients receiving KEYTRUDA plus chemotherapy, with or without bevacizumab, including 3 cases of haemorrhage, 2 cases of sepsis, 2 cases due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection.
  • In RCC in Combination with axitinib (KEYNOTE-426) the most common adverse reactions [all Grades (≥20%)] with KEYTRUDA in combination with axitinib were: diarrhoea (56%), fatigue/asthenia (52%), hypertension (48%), hypothyroidism (35%), decreased appetite (30%), hepatotoxicity (39%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%) and constipation (21%). Incidences of Grades 3–5 adverse reactions were 76% for KEYTRUDA combination therapy and 71% for sunitinib alone.
  • In the adjuvant treatment of Resected RCC (KEYNOTE-564), when KEYTRUDA was administered as monotherapy, adverse events were generally similar to those occurring in patients with melanoma or NSCLC.
  • In RCC in combination with lenvatinib (KEYNOTE-581) the most common adverse events [all Grades (≥20%) and at a higher incidence than in the sunitinib arm (between arm difference of ≥5%)] with KEYTRUDA in combination with lenvatinib were: diarrhoea (61%), hypertension (55%), hypothyroidism (47%), decreased appetite (40%), nausea (36%), dysphonia (30%), decreased weight (30%), proteinuria (30%), arthralgia (28%), rash (27%), vomiting (26%), constipation (25%), headache (23%), and abdominal pain (21%).
  • In Recurrent or Metastatic cSCC or LA cSCC, adverse events were generally similar to those occurring in patients with melanoma or NSCLC.
  • In Oesophageal Cancer (KEYNOTE-590) adverse reactions occurring in at least 20% of patients and at a higher incidence (≥2%) of Grades 3–5 severity for KEYTRUDA in combination with chemotherapy (cisplatin and 5-FU) compared to placebo and chemotherapy (cisplatin and 5-FU) were: vomiting (7% vs 5%), stomatitis (6% vs 3.8%), neutrophil count decreased (24.1% vs 17.3%), and white blood cell count decreased (9.2% vs 4.9%).
  • In TMB-H Cancer (KEYNOTE-158) adverse reactions were similar to those occurring in patients with other solid tumours who received KEYTRUDA as a single agent.
  • In High-Risk Early-Stage TNBC (KEYNOTE-522), the most common adverse events [all Grades (≥20%)] for those receiving KEYTRUDA in combination with chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide), given as a neoadjuvant treatment followed by surgery then continued alone as adjuvant treatment, were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), peripheral neuropathy (41%), diarrhoea (41%), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%).
  • In Locally Recurrent Unresectable or Metastatic TNBC (KEYNOTE-355), the most common adverse events [all Grades (≥20%)] for those receiving KEYTRUDA in combination with chemotherapy (paclitaxel, nab-paclitaxel, or gemcitabine and carboplatin), were fatigue (48%), nausea (44%), alopecia (34%), diarrhoea (28%), constipation (28%), vomiting (26%), rash (26%), cough (23%), decreased appetite (21%), and headache (20%).

Geriatric Patients

No overall differences in safety or efficacy were reported between elderly patients (65 years and over) and younger patients (less than 65 years). No dose adjustment is necessary in this population.

For combination therapy with KEYTRUDA and axitinib in patients with advanced RCC, limited safety data is available regarding patients ≥75 years of age.

Renal Insufficiency

No dose adjustment is needed for patients with mild or moderate renal impairment. KEYTRUDA has not been studied in patients with severe renal impairment.

Hepatic Insufficiency

No dose adjustment is needed for patients with mild hepatic impairment. KEYTRUDA has not been studied in patients with moderate or severe hepatic impairment.

INDICATIONS

▼This medicinal product is subject to additional monitoring in Australia due to provisional approval of an extension of indication. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse events at www.tga.gov.au/reporting-problems.

Melanoma

KEYTRUDA is indicated as monotherapy for the treatment of unresectable or metastatic melanoma in adults.

KEYTRUDA is indicated for the adjuvant treatment of adult and adolescent (12 years and older) patients with Stage IIB, IIC, or III melanoma who have undergone complete resection.

Non-small Cell Lung Cancer (NSCLC)

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic non-squamous NSCLC, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumour aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA is indicated as monotherapy for the first-line treatment of patients with NSCLC expressing programmed death receptor-ligand 1 (PD-L1) [tumour proportion score (TPS) ≥1%] as determined by a validated test, with no EGFR or ALK genomic tumour aberrations, and is:

  • Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or –
  • Metastatic

KEYTRUDA is indicated as monotherapy for the treatment of patients with advanced NSCLC whose tumours express PD-L1 with a ≥1% TPS as determined by a validated test and who have received platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumour aberrations should have received prior therapy for these aberrations prior to receiving KEYTRUDA.

KEYTRUDA is indicated as monotherapy for the adjuvant treatment of patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC who have undergone complete resection and platinum-based chemotherapy.

Head and Neck Squamous Cell Cancer (HNSCC)

KEYTRUDA, as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, is indicated for the first-line treatment of patients with metastatic or unresectable recurrent HNSCC, and whose tumours express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by a validated test.

KEYTRUDA is indicated as monotherapy for the treatment of patients with metastatic or unresectable recurrent HNSCC with disease progression on or after platinum-containing chemotherapy and whose tumours express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by a validated test.

Classical Hodgkin Lymphoma (cHL)

KEYTRUDA is indicated as monotherapy for the treatment of adult and paediatric patients with relapsed or refractory cHL:

1. Following autologous stem cell transplant (ASCT) or

2. Following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option.

The approval of this indication in paediatric patients is on the basis of objective response rate from patients aged 11 years and older from single arm trial data and extrapolation from adult data.

Primary Mediastinal B-Cell Lymphoma (PMBCL)

KEYTRUDA is indicated for the treatment of adult and paediatric patients with refractory primary PMBCL, or who have relapsed after 2 or more prior lines of therapy. The approval of this indication is on the basis of objective response rate (ORR) and duration of response from non-randomised studies.

Urothelial Carcinoma

KEYTRUDA is indicated as monotherapy for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for any platinum-containing chemotherapy. This indication is approved based on overall response rate and duration of response in a single-arm study. Improvements in overall survival, progression-free survival, or health-related quality of life have not been established.

KEYTRUDA is indicated as monotherapy for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have received platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, highrisk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in-situ (CIS) with or without papillary tumours who are ineligible for or have elected not to undergo cystectomy. This indication was approved via the provisional approval pathway based on complete response rate and duration of response. Continued approval of this indication depends on verification and description of benefit in confirmatory trials.

Microsatellite Instability High (MSI-H) or Mismatch Repair Deficient (dMMR) Cancer

KEYTRUDA is indicated for the treatment of adult and paediatric patients with unresectable or metastatic solid tumours that are MSI-H or dMMR, as determined by a validated test, that have progressed following prior treatment and when there are no satisfactory alternative treatment options.
Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Colorectal Cancer KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic colorectal cancer (CRC) that is MSI-H or dMMR as determined by a validated test.

Endometrial Carcinoma

KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Cervical Cancer

KEYTRUDA, in combination with platinum chemotherapy and paclitaxel, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumours express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by a validated test.

Renal Cell Carcinoma (RCC)

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced RCC.

KEYTRUDA, in combination with lenvatinib, is indicated for the first-line treatment of adult patients with advanced RCC.

KEYTRUDA, as monotherapy, is indicated for the adjuvant treatment of patients with RCC with a clear cell component who are at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

Cutaneous Squamous Cell Carcinoma (cSCC)

KEYTRUDA is indicated as monotherapy for the treatment of adult patients with recurrent or metastatic cSCC or locally advanced cSCC that is not curable by surgery or radiation. This indication was approved via the provisional approval pathway based on objective response rate and duration of response from a single-arm study. Improvements in overall survival, progression-free survival, or health-related quality of life have not been established. Full registration for this indication depends on submission of further clinical data to confirm the clinical benefit of the medicine.

Oesophageal Cancer

KEYTRUDA, in combination with platinum and fluoropyrimidine based chemotherapy, is indicated for the firstline treatment of patients with locally advanced or metastatic carcinoma of the oesophagus or HER2 negative gastroesophageal junction adenocarcinoma (tumour centre 1 to 5 centimetres above the gastroesophageal junction) that is not amenable to surgical resection or definitive chemoradiation.

Tumour Mutational Burden-High (TMB-H) Cancer

KEYTRUDA is indicated for the treatment of adult and paediatric patients with unresectable or metastatic tumour mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumours, as determined by a validated test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication was approved via the provisional approval pathway, based on the pooling of data on objective response rate and response duration across multiple different tissue types in a single-arm trial. The assumption that TMB-H status is predictive of the treatment effect of KEYTRUDA for every tissue type has not been verified. Full registration for this indication depends on verification and description of clinical benefit in confirmatory trials.

Triple-Negative Breast Cancer (TNBC)

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumours express PD-L1 (CPS ≥10) as determined by a validated test and who have not received prior chemotherapy for metastatic disease.

CONTRAINDICATIONS

None.

AU-KEY-01486 v2.0. Issued July 2024.