Pembrolizumab for dMMR/MSI-H tumors marks first tumor agnostic FDA approval

The United States Food and Drug Administration’s approval earlier this year of pembrolizumab marks the first tumor agnostic indication for a cancer drug.^1,2 Accelerated approval was granted for the treatment of adult and pediatric patients with any unresectable or metastatic solid tumor that displays mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) and who have progressed after previous treatment and have no satisfactory alternatives. It is also approved specifically for patients with MSI-H or dMMR colorectal cancer (CRC) that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Pembrolizumab is a programmed cell death protein-1 (PD-1) receptor inhibitor that blocks the interaction between PD-1 and its ligand, PD-L1, restoring the activity of tumor-infiltrating T cells and boosting the anti-tumor immune response. It is thought to be particularly effective in dMMR/MSI-H tumors because they have a high mutational load and therefore display an abundance of antigens on their surfaces to provoke an immune response.

Approval for the drug was based on the demonstration of durable responses in 149 patients with MSI-H or dMMR cancers across 5 uncontrolled, multicohort, multicenter, single-arm trials. In all, 90 of the patients had CRC, and the remaining 59 patients had 1 of 14 other cancer types that included endometrial, biliary, gastric or gastroesophageal, pancreatic, and breast cancers.

Patients in these trials received pembrolizumab at 1 of 2 different doses, either 200 mg every 3 weeks or 10 mg/kg every 2 weeks, until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, or coincided with a decline in performance status. Treatment was administered for a maximum of 2 years. Patients with an active autoimmune disease or a medical condition that required immunosuppression were ineligible for treatment in all 5 studies.

The median age of enrolled patients was 55 years; 56% were men; 77% white, 19% Asian, 2% black; 98% had metastatic or unresectable disease; and all had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (range, 0-5, where 0 denotes full activity and 1, restricted in physically strenuous activity but ambulatory). MSI-H and MMR status were identified prospectively using polymerase chain reaction and immunohistochemical analyses, respectively.

The primary endpoint was objective response rate (ORR), according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), as assessed by blinded independent central radiologist review, and response duration. The ORR across all five studies was 36.9% and, among 78% of patients who responded, the responses lasted 6 months or more. There were 11 complete responses (CRs) and 48 partial responses (PRs) and response rates were similar across tumor types.

The safety profile was consistent with previously reported safety data for pembrolizumab. The most common adverse events included fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation, and nausea.

The prescribing information includes a “limitation of use” that states that pembroliumab’s safety and efficacy haven’t been established in pediatric patients with MSI-H cancers of the central nervous system.³ It also details warnings and precautions about immune-mediated toxicities, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and renal dysfunction, among others.

Patients should be monitored for signs and symptoms of these toxicities and treated appropriately. Treatment should be withheld and corticosteroids should be administered for grade 2 or higher pneumonitis, colitis, hepatitis, and nephritis; and corticosteroids and hormone replacement as clinically indicated for endocrinopathies. It should also be withheld for aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >3-5 times the upper limit of normal (ULN) or total bilirubin levels >1.5-3 times ULN.

Pembrolizumab should be permanently discontinued upon grade 3, 4, or recurrent grade 2 pneumonitis, colitis, nephritis/renal dysfunction, and endocrinopathies or for AST or ALT levels >5 times ULN or total bilirubin levels >3 times ULN. For patients with liver metastases who begin treatment with grade 2 AST or ALT, treatment should be permanently discontinued following increases of more than 50%, relative to baseline, that last for at least 1 week.

Health care providers should also bear in mind that pembrolizumab can, more rarely, cause other immune-mediated toxicities, such as arthritis and exfoliative rash that may require treatment and, based on its mechanism of action, pembrolizumab can also cause fetal harm. Patients with reproductive potential should be advised of the implications. Pembrolizumab is marketed as Keytruda by Merck & Co Inc.

The United States Food and Drug Administration’s approval earlier this year of pembrolizumab marks the first tumor agnostic indication for a cancer drug.^1,2 Accelerated approval was granted for the treatment of adult and pediatric patients with any unresectable or metastatic solid tumor that displays mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) and who have progressed after previous treatment and have no satisfactory alternatives. It is also approved specifically for patients with MSI-H or dMMR colorectal cancer (CRC) that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Pembrolizumab is a programmed cell death protein-1 (PD-1) receptor inhibitor that blocks the interaction between PD-1 and its ligand, PD-L1, restoring the activity of tumor-infiltrating T cells and boosting the anti-tumor immune response. It is thought to be particularly effective in dMMR/MSI-H tumors because they have a high mutational load and therefore display an abundance of antigens on their surfaces to provoke an immune response.

Approval for the drug was based on the demonstration of durable responses in 149 patients with MSI-H or dMMR cancers across 5 uncontrolled, multicohort, multicenter, single-arm trials. In all, 90 of the patients had CRC, and the remaining 59 patients had 1 of 14 other cancer types that included endometrial, biliary, gastric or gastroesophageal, pancreatic, and breast cancers.

Patients in these trials received pembrolizumab at 1 of 2 different doses, either 200 mg every 3 weeks or 10 mg/kg every 2 weeks, until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, or coincided with a decline in performance status. Treatment was administered for a maximum of 2 years. Patients with an active autoimmune disease or a medical condition that required immunosuppression were ineligible for treatment in all 5 studies.

The median age of enrolled patients was 55 years; 56% were men; 77% white, 19% Asian, 2% black; 98% had metastatic or unresectable disease; and all had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (range, 0-5, where 0 denotes full activity and 1, restricted in physically strenuous activity but ambulatory). MSI-H and MMR status were identified prospectively using polymerase chain reaction and immunohistochemical analyses, respectively.

The primary endpoint was objective response rate (ORR), according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), as assessed by blinded independent central radiologist review, and response duration. The ORR across all five studies was 36.9% and, among 78% of patients who responded, the responses lasted 6 months or more. There were 11 complete responses (CRs) and 48 partial responses (PRs) and response rates were similar across tumor types.

The safety profile was consistent with previously reported safety data for pembrolizumab. The most common adverse events included fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation, and nausea.

The prescribing information includes a “limitation of use” that states that pembroliumab’s safety and efficacy haven’t been established in pediatric patients with MSI-H cancers of the central nervous system.³ It also details warnings and precautions about immune-mediated toxicities, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and renal dysfunction, among others.

Patients should be monitored for signs and symptoms of these toxicities and treated appropriately. Treatment should be withheld and corticosteroids should be administered for grade 2 or higher pneumonitis, colitis, hepatitis, and nephritis; and corticosteroids and hormone replacement as clinically indicated for endocrinopathies. It should also be withheld for aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >3-5 times the upper limit of normal (ULN) or total bilirubin levels >1.5-3 times ULN.

Pembrolizumab should be permanently discontinued upon grade 3, 4, or recurrent grade 2 pneumonitis, colitis, nephritis/renal dysfunction, and endocrinopathies or for AST or ALT levels >5 times ULN or total bilirubin levels >3 times ULN. For patients with liver metastases who begin treatment with grade 2 AST or ALT, treatment should be permanently discontinued following increases of more than 50%, relative to baseline, that last for at least 1 week.

Health care providers should also bear in mind that pembrolizumab can, more rarely, cause other immune-mediated toxicities, such as arthritis and exfoliative rash that may require treatment and, based on its mechanism of action, pembrolizumab can also cause fetal harm. Patients with reproductive potential should be advised of the implications. Pembrolizumab is marketed as Keytruda by Merck & Co Inc.

The United States Food and Drug Administration’s approval earlier this year of pembrolizumab marks the first tumor agnostic indication for a cancer drug.^1,2 Accelerated approval was granted for the treatment of adult and pediatric patients with any unresectable or metastatic solid tumor that displays mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) and who have progressed after previous treatment and have no satisfactory alternatives. It is also approved specifically for patients with MSI-H or dMMR colorectal cancer (CRC) that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Pembrolizumab is a programmed cell death protein-1 (PD-1) receptor inhibitor that blocks the interaction between PD-1 and its ligand, PD-L1, restoring the activity of tumor-infiltrating T cells and boosting the anti-tumor immune response. It is thought to be particularly effective in dMMR/MSI-H tumors because they have a high mutational load and therefore display an abundance of antigens on their surfaces to provoke an immune response.

Approval for the drug was based on the demonstration of durable responses in 149 patients with MSI-H or dMMR cancers across 5 uncontrolled, multicohort, multicenter, single-arm trials. In all, 90 of the patients had CRC, and the remaining 59 patients had 1 of 14 other cancer types that included endometrial, biliary, gastric or gastroesophageal, pancreatic, and breast cancers.

Patients in these trials received pembrolizumab at 1 of 2 different doses, either 200 mg every 3 weeks or 10 mg/kg every 2 weeks, until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, or coincided with a decline in performance status. Treatment was administered for a maximum of 2 years. Patients with an active autoimmune disease or a medical condition that required immunosuppression were ineligible for treatment in all 5 studies.

The median age of enrolled patients was 55 years; 56% were men; 77% white, 19% Asian, 2% black; 98% had metastatic or unresectable disease; and all had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (range, 0-5, where 0 denotes full activity and 1, restricted in physically strenuous activity but ambulatory). MSI-H and MMR status were identified prospectively using polymerase chain reaction and immunohistochemical analyses, respectively.

The primary endpoint was objective response rate (ORR), according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), as assessed by blinded independent central radiologist review, and response duration. The ORR across all five studies was 36.9% and, among 78% of patients who responded, the responses lasted 6 months or more. There were 11 complete responses (CRs) and 48 partial responses (PRs) and response rates were similar across tumor types.

The safety profile was consistent with previously reported safety data for pembrolizumab. The most common adverse events included fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation, and nausea.

The prescribing information includes a “limitation of use” that states that pembroliumab’s safety and efficacy haven’t been established in pediatric patients with MSI-H cancers of the central nervous system.³ It also details warnings and precautions about immune-mediated toxicities, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and renal dysfunction, among others.

Patients should be monitored for signs and symptoms of these toxicities and treated appropriately. Treatment should be withheld and corticosteroids should be administered for grade 2 or higher pneumonitis, colitis, hepatitis, and nephritis; and corticosteroids and hormone replacement as clinically indicated for endocrinopathies. It should also be withheld for aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >3-5 times the upper limit of normal (ULN) or total bilirubin levels >1.5-3 times ULN.

Pembrolizumab should be permanently discontinued upon grade 3, 4, or recurrent grade 2 pneumonitis, colitis, nephritis/renal dysfunction, and endocrinopathies or for AST or ALT levels >5 times ULN or total bilirubin levels >3 times ULN. For patients with liver metastases who begin treatment with grade 2 AST or ALT, treatment should be permanently discontinued following increases of more than 50%, relative to baseline, that last for at least 1 week.

Health care providers should also bear in mind that pembrolizumab can, more rarely, cause other immune-mediated toxicities, such as arthritis and exfoliative rash that may require treatment and, based on its mechanism of action, pembrolizumab can also cause fetal harm. Patients with reproductive potential should be advised of the implications. Pembrolizumab is marketed as Keytruda by Merck & Co Inc.