Tumours harness several strategies to avoid elimination by the immune system and exploiting the programmed cell death protein (PD1) is a key component. Studies have shown that the expression of PD1 by tumour-infiltrating lymphocytes is associated with diminished effector function. The impaired proliferation, production and exhaustion of effector T-cells suppress the body’s regulatory cytotoxic response against tumour cells. Expression of the ligands for PD1, known as PD-L1 and PD-L2, has been observed in many tumour types. Notably, tumour PD-L1 expression is associated with larger tumour size or an increased risk of poorer outcomes in terms of progression-free survival (PFS) or overall survival (OS).
Immune checkpoint inhibitors were thus designed to address this complex interplay between the immune system and developing tumours. This pharmacological strategy aims to restore the body’s anti-tumour immune response and reduce or destroy the immunosuppressive microenvironment of the tumour.
Introduction to Pembrolizumab (Keytruda)
Pembrolizumab (Keytruda) was developed as a highly selective humanized monoclonal anti-PD1 antibody. It is designed to disrupt the engagement of PD1 with its ligands, PD-L1 and PD-L2, thereby blocking inhibitor signals in T-cells. This therapeutic agent has been extensively investigated in numerous malignancies, either alone or in combination with other chemotherapies, leading to a prodigious body of clinical evidence. Other PD1 inhibitors approved by the US FDA include nivolumab (Opdivo) and Cemiplimab (Libtayo).
Pembrolizumab’s Drug Profile, Indications and Key Trials
Immune evasion is a recognised hallmark of cancer and the subject of significant research investment. KEYNOTE is a comprehensive immune-oncology global clinical research programme that includes over 1,700 trials studying pembrolizumab across a wide variety of cancers and treatment settings. The drug is currently standard of care in the treatment of several malignancies, and ongoing trials continue to inform its rapidly expanding use, advancing treatment and outcomes for patients.
In Singapore, the Health Sciences Authority (HSA) have granted market authorisation for its use in 10 cancers which include melanoma, non-small cell lung carcinoma (NSCLC), head and neck cancer, classical Hodgkin Lymphoma (cHL), urothelial carcinoma, oesophageal carcinoma, colorectal cancer (CRC), renal cell carcinoma (RCC), endometrial carcinoma and triple-negative breast cancer (TNBC).
Each single-use vial contains 100mg/4mL of drug that requires cold-chain storage and reconstitution for administration as an intravenous solution. A summary of its approved indications and select trials within the monumental KEYNOTE portfolio is detailed in Table 1.
From a safety perspective, pembrolizumab has an acceptable tolerability profile and common adverse events (AE) reported include fatigue, rash, pruritus, arthralgia, amylase elevation, and diarrhoea. Notably, its use is associated with immune-related AEs which include colitis, hepatitis, endocrinopathies, pneumonitis, and nephritis. Immune-related reactions are related to its mechanism of action but have proven generally manageable or reversible, with the support of clinical guidelines.
Table 1: HSA-Labelled Indications and Key Trials
| Cancer |
HSA-labelled indications |
Key trials |
| Melanoma |
- Treatment of unresectable or metastatic melanoma
- Adjuvant treatment of melanoma with lymph node involvement who have undergone complete resection
|
- KEYNOTE-006: RCT for unresectable or metastatic melanoma treatment naïve to ipilimumab
- KEYNOTE-002: RCT for unresectable or metastatic melanoma previously treated with ipilimumab
- KEYNOTE-001: Open-label study for unresectable or metastatic melanoma
- KEYNOTE-054: Placebo-controlled trial for the adjuvant treatment of completely resected melanoma
|
| Non-small cell lung carcinoma (NSCLC) |
- First-line treatment, in combination with pemetrexed and platinum chemotherapy, for metastatic non-squamous NSCLC with EGFR or ALK genomic tumour combinations
- First-line treatment, in combination with carboplatin and either paclitaxel or nab-paclitaxel, for metastatic squamous NSCLC
- First-line monotherapy in metastatic NSCLC, with tumours that express PD-L1 with a ≥ 50% tumour proportion score (TPS), with no EGFR or ALK genomic tumour aberrations
- Monotherapy in locally advanced or metastatic NSCLC whose tumours express PD-L1 with a ≥1% TPS, who have received platinum-containing chemotherapy
|
- KEYNOTE-189: RCT of combination therapy (with pemetrexed + platinum) in treatment-naïve non-squamous NSCLC, with no EGFR/ ALK tumour aberrations
- KEYNOTE-407: RCT of combination therapy (with carboplatin and either paclitaxel or nab-paclitaxel) in treatment-naïve squamous NSCLC
- KEYNOTE-024: RCT of treatment-naïve metastatic NSCLC with PD-L1 TPS ≥ 50% and no EGFR/ ALK tumour aberrations
- KEYNOTE-042: RCT of treatment naïve advanced NSCLC with PD-L1 TPS ≥ 1% with no EGFR or ALK alterations
- KEYNOTE-010: RCT of advanced NSCLC (PD-L1 TPS ≥ 1%) that progressed following platinum-containing chemotherapy
- KEYNOTE-001: Open-label study for unresectable or metastatic melanoma with the progression of disease following platinum-containing chemotherapy
|
| Head and neck cancer |
- First-line treatment, as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, for metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) whose tumours express PD-L1 with a combined positive score (CPS) ≥ 1
|
- KEYNOTE-048: RCT of first-line monotherapy or combination therapy in treatment-naïve recurrent or metastatic HNSCC
|
| Classical Hodgkin lymphoma (cHL) |
- Adult and paediatric patients (aged ≥ 3 years) with relapsed or refractory cHL, who have failed autologous stem cell transplant (ASCT) or followed at least two prior therapies with ASCT is not a treatment option
|
|
| Urothelial carcinoma |
- Locally advanced or metastatic urothelial carcinoma whose tumours express PD-L1 with a CPS ≥ 10, and who are not eligible for cisplatin-containing chemotherapy
- Locally advanced or metastatic urothelial carcinoma who have received prior platinum-containing chemotherapy
|
- KEYNOTE-045: RCT in locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy
- KEYNOTE-052: Open-label trial in locally advanced or metastatic urothelial carcinoma, ineligible for cisplatin-containing chemotherapy
|
| Oesophageal cancer |
- First-line treatment, in combination with platinum and fluoropyrimidine-based chemotherapy, of locally advanced or metastatic carcinoma of the oesophagus or HER2 negative gastroesophageal junction (GEJ) adenocarcinoma (tumours with epicentre 1 to 5 centimetres above the GEJ) that is not amenable to surgical resection or definitive chemoradiation
|
- KEYNOTE-590: RCT for first-line treatment in locally advanced unresectable or metastatic oesophageal cancer
|
| Colorectal cancer (CRC) |
- First-line treatment of metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) CRC
|
- KEYNOTE-177: RCT for first-line treatment in metastatic MSI-H or dMMR CRC
|
| Renal cell carcinoma (RCC) |
- First-line treatment, in combination with axitinib, of advanced RCC
|
- KEYNOTE-426: RCT of combination therapy in advanced RCC naïve to treatment
|
| Endometrial carcinoma |
- Used in combination with Lenvatinib for the treatment of advanced endometrial carcinoma (that is not MSI-H or dMMR) who have disease progression following prior chemotherapy in the metastatic setting and are not candidates for curative surgery or radiation
|
- KEYNOTE-146: Combination therapy open-label study in metastatic endometrial carcinoma that progressed following at least one prior systemic therapy
|
| Triple-negative breast cancer (TNBC) |
- In combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic TNBC whose tumours express PD-L1 (CPS ≥ 10) and who have not received prior chemotherapy for metastatic disease
|
- KEYNOTE-355: RCT of combination therapy in locally recurrent unresectable or metastatic TNBC, which had not been previously treated with chemotherapy
|
