Lung cancer is the leading cause of deaths with 1.88 million cases and ranks fifth in the incidence of cancer in human (3.34 million) according to 2017 statistics worldwide and emerges as a global health burden.
Journal of military pharmaco-medicine no8-2019 THE ROLE OF IMMUNE CHECKPOINT INHIBITOR PEMBROLIZUMAB IN TREATMENT OF PATIENTS WITH NON-SMALL CELL LUNG CANCER: REVIEW Pham Thi Kim Nhung1; Ta Ba Thang1; Dao Ngoc Bang1 SUMMARY Lung cancer is the leading cause of deaths with 1.88 million cases and ranks fifth in the incidence of cancer in human (3.34 million) according to 2017 statistics worldwide and emerges as a global health burden Immunotherapy, especially using immune checkpoint inhibitors has opened novel therapeutic opportunities that are effective for patients with advanced stage of lung cancer, who poorly responds or does not respond to chemoradiation therapy Pembrolizumab (keytruda) is a monoclonal antibody against PD-1 on surface of T-lymphocytes that have been shown improvement of overall survival, progression-free survival and mortality in non-small cell lung cancer patients based on the results of a series of clinical trials such as Keynote 010, 024, 021, 042, 189, 407 This is also the scientific basis for indication of keytruda that was approved by the United States Food and Drug Administration * Keywords: Non-small cell lung cancer; PD-1; Pembrolizumab IMMUNE CHECKPOINT INHIBITOR DRUGS AND MECHANISM OF PEMBROLIZUMAB (KEYTRUDA) Immunotherapy is becoming increasingly an effective treatment in malignant diseases It differs from other methods such as surgery, chemotherapy, radiotherapy, targeted therapy in enhancing action of the immune system to fight against cancer cells by a “natural” way In the past, immunotherapy in cancer treatment was mainly non-specific viaenhancing the function of the general immune system or reducing the favorable micro-environment for the development and spread of cancer cells, such as vaccination against viruses that can lead to cancer, using cytokines (IL-2, IFN) as an mediator… Currently, specific immunotherapy is focused on helping the component of the patient’s immune system to identify cancer cell easier and improve the effectiveness of immune response killing cancer cells such as using monoclonal antibodies (mAbs) or using of modified immune cells 103 Military Hospital Corresponding author: Pham Thi Kim Nhung (khanhnhu106@gmail.com) Date received: 09/09/2019 Date accepted: 15/10/2019 218 Journal of military pharmaco-medicine no8-2019 Monoclonal antibodies are the most common passive immunotherapy with many types of antibodies approved by the United States Food and Drug Administration These antibodies can attack cancer cells directly or attach specific protein on cancer cells that help to transport chemotherapy or radiotherapy, or flag cancer cells to the immune system to recognize and destroy In addition, monoclonal antibodies can release or “unlock” immune checkpoint inhibitor so that the immune system becomes activated and perform the function of killing cancer cells Immune checkpoints are surface receptors which regulate cell signals and inhibit immune activity of T lymphocytes In cancerous microenvironment, cancer cells often express CTLA-4 ligand, PD-L1 ligand, thereby inhibiting T cell activity As a result, immune checkpoint inhibitor drugs will be a potential approach for cancer immunotherapy PD-1 (programmed cell death receptor 1) is an immunosuppressant receptor defined after CTLA-4 This receptor has ligands (PD-L1 or B7-H1 or CD274) and PD-L2 or B7-DC or CD273) [1] Although the interaction between PD-L2 and PD-1 is - times higher than PD-L1 and PD-1, PD-L1 is still the main ligand of PD-1 [2] PD-1 is a negative regulatory receptor, expressed only on the surface of activated T lymphocytes while its ligands (PD-L1 and PD-L2) can be expressed in tumor cells under the action of cytokines and interferons produced by activated T cells or soluble in serum The interaction of PD-L1 with the PD-1 receptor transmits an immunosuppressive signal to the T cell, resulting in an inactivated status of T cell or inhibited T cells PD-1 also inhibits T cell activity by reducing the activating signal of the CD28 receptor, inhibiting the activity of the CD28 receptor PD-1 mainly controls the activity of activated T cell in peripheral tissues In addition, PD-1/PD-L1 pathway is also thought to play a role in controlling the T cell invasion into the tumor, hence preventing the direct contact of activated T cells and cancer cells [3] Therefore, monoclonal antibodies against PD-1 or PD-L1 will interact with PD-1 or PD-L1 respectively, helping to reactivate T cell PD-L1 is a type transmembrane protein (B7-H1); PD-L1 expression in tumor cells promotes regulations and self-tolerance of immune system by eliminating tumor cells by binding to T lymphocyte Mechanism of “escaping” the control of immune system of the tumor cells: The immune system plays an important dual role in cancer through the process of immune repair Both the innate and adaptive immune system inhibit tumor growth and kill cancer cells during the elimination phage or immuno-surveillance However, tumor cells are able to escape this elimination phase by a variety of mechanisms such as creating a local immunosuppressive state, producing cytokines that have an immunosuppressive function, creating defects in the presentation of tumor antigens to T cell or expression of molecules that regulate immune check point like CTLA-4, PD-1 and PD-L1 Hence, tumor cells disrupt normal 219 Journal of military pharmaco-medicine no8-2019 immune function to create favorable conditions for tumor cells to grow For example, the heterozygous loss of HLA (human leukocyte antigen) appearing in approximately 40% of patients with early stage non-small cell lung cancer (NSCLC) is a special manifestation of “escaping” One of the cancer therapeutic strategies to combat “escaping” is to reactivate T cell mediated antitumor activity by modulating the interaction between the receptor and the ligand of immune checkpoint In normal conditions, the receptor of immune check point has the function of limiting the activity of T cell, preventing the destruction of normal cells, creating balance Mechanism of pembrolizumab (keytruda): pembrolizumab is a monoclonal antibody against the PD-1 receptor on the surface of T cell Until now, there have been many applications of immune checkpoint inhibitor drugs in cancer treatment such as NSCLC, colorectal cancer, stomach cancer, cervical cancer, kidney cancer, melanoma… However, for NSCLC, pembrolizumab (keytruda) and nivolumab (opdivo), atezolizumab (tecentriq) are the main choice CLINICAL STUDIES/TRIALS ON THE EFFECTIVENESS OF PEMBROLIZUMAB (KEYTRUDA) ON NSCLC General information Pembrolizumab (keytruda) is a product of MSD company This drug has been applied in a series of clinical trials such as Keynote 010, 024, 021, 042, 189, 407 and has shown positive results, opening up new opportunities for patients with 220 NSCLC It is also the scientific basis for keytruda’s indications for this group of patients Clinical trials KEYNOTE 010 is a randomized, openlabel, phase 2/3 study that evaluate the efficacy of keytruda compared with standard chemotherapy in 1,034 advanced stage NSCLC patients, progression after platinum regimen with PD-L1 expression on at least 1% Patients were randomly assigned (1:1:1) in groups: 345 patients received pembrolizumab mg/kg every weeks; 346 patients received pembrolizumab 10 mg/kg every weeks and 343 patients received docetaxel 75 mg/m2 every weeks In addition, the number of patients with high PD-L1 expression (TPS ≥ 50%) were 139, 151 and 152 in groups, respectively The endpoints were overall survival and progression free survival, rate of complete response and time of response [4] In this trial, treatment was discontinued for adverse reactions in 8% of the 682 patients receiving keytruda across both doses The most common adverse events resulting in permanent discontinuation of keytruda occurred in 23% of patients, the most common were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decrease appetite (1.3%) and pneumonitis (1%) Grade - treatment - related adverse events were less common with pembrolizumab than with docetaxel (43 of 339 patients (13%) received mg/kg, 55 of 343 patients (16%) received 10 mg/kg, and 109 of 309 patients (35%) received docetaxel In the total population, median overall survival was Journal of military pharmaco-medicine no8-2019 10.4 months with pembrolizumab mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel Overall survival was significantly longer for pembrolizumab mg/kg versus docetaxel (hazard ratio [HR] 0.71, 95%CI: 0.58 - 0.88; p = 0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (0.61, 0.49 - 0.75; p < 0.0001) Median progression-free survival was 3.9 months with pembrolizumab mg/kg, 4.0 months with pembrolizumab 10 mg/kg, and 4.0 months with docetaxel, with no significant difference in pembrolizumab mg/kg versus docetaxel (0.88, 0.74 1.05; p = 0.07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0.79, 95%CI: 0.66 - 0.94; p = 0.004) Among patients with at least 50% of tumor cells expressing PD-L1, overall survival was significantly longer with pembrolizumab mg/kg than with docetaxel (median 14.9 months vs 8.2 months; HR 0.54, 95%CI: 0.38 - 0.77; p = 0.0002) and with pembrolizumab 10 mg/kg than with docetaxel (17.3 months vs 8.2 months; 0.50, 0.36 - 0.70; p < 0.0001) Likewise, for this patient population, progressionfree survival was significantly longer with pembrolizumab mg/kg than with docetaxel (median 5.0 months vs 4.1 months; HR 0.59, 95%CI: 0.44 - 0.78; p = 0.0001) and with pembrolizumab mg/kg than with docetaxel (5.2 months vs 4.1 months; 0.59, 0.45 - 0.78; p < 0.0001) Keytruda was approved for treatment of advanced stage NSCLC with the fix dose of 200 mg every weeks until disease progression or unacceptable toxicity or up to 24 months in patients without disease progression [5] KEYNOTE 042 is a randomized, multicenter, open-label, active-controlled trial conducted in large scale of 32 countries, in 21 centers in 1,274 patients with stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC and whose tumors expressed PD-L1 (TPS ≥ 1%) and who had not received prior systemic treatment for metastatic NSCLC, no EGFR or ALK genomic tumor aberration Patients were randomized (1:1) to receive keytruda 200 mg intravenously every three weeks up to 35 cycles (n = 637) or investigator’s choice of either of the following chemotherapy regimens (n = 637): pemetrexed 500 mg/m2 or paclitaxel 200 mg/m2 and carboplatin AUC to mg/mL/min every three weeks on day for a maximum of cycles followed by optional pemetrexed 500 mg/m2 every three weeks for patients with nonsquamous histologies PD-L1 expression detected by IHC: 599/1,274 patients (47%) with PD-L1 expression TPS ≥ 50%; 818/1,274 patients (64%) with PD-L1 TPS ≥ 20% Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥ 50% HR 0.69, 95%CI: 0.56 - 0.85, p = 0.0003; ≥ 20% 0.77, 0.64 - 0.92, p = 0.0020, and ≥ 1% 0.81, 0.71 - 0.93, p = 0.0018) The median survival values by TPS population were 20.0 months (95%CI: 15.4 - 24.9) for pembrolizumab versus 12.2 months (10.4 14.2) for chemotherapy, 17.7 months (15.3 - 22.1) versus 13.0 months (11.6 - 15.3), and 16.7 months (13.9 - 19.7) versus 12.1 months (11.3 - 13.3), 221 Journal of military pharmaco-medicine no8-2019 respectively Treatment-related adverse events of grade or worse occurred in 113 of 636 patients (18%) treated in the pembrolizumab group and in 252 of 615 patients (41%) in the chemotherapy group and led to death in 13 patients (2%) and 14 patients (2%), respectively The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic nonsmall-cell lung cancer without sensitizing EGFR or ALK alterations and with low PD-L1 TPS [6] KEYNOTE 024 is a randomized, openlabel, phase study evaluating keytruda monotherapy compared to standard of care (SOC) platinum-containing chemotherapy for the treatment of patients with both squamous (18%) and non-squamous (82%) metastatic NSCLC The study enrolled patients who had not received prior systemic chemotherapy treatment and whose tumors had high PD-L1 expression (TPS ≥ 50%) and with no EGFR or ALK aberrations 305 patients randomized receive keytruda 200 mg every weeks or investigator-choice SOC platinum-based chemotherapy (pemetrexed + carboplatin, pemetrexed + cisplatin, gemcitabin + cisplatin, gemcitabin + carboplatin or paclitaxel + carboplatin) Pemetrexed maintenance therapy was permitted for patients with non squamous histologies The primary endpoint was progression free survival (PFS), overall survival (OS) and objective response rate (ORR) [7] At May 2016, the trial was followed 11.2 months There were 189 patients progressive or died Median PFS was 10.3 months (95%CI: 222 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95%CI: 4.2 - 6.2) in the chemotherapy group The estimated percentage of patients who were alive and had no disease progression at months was 62.1% (95%CI: 53.8 - 69.4) in the pembrolizumab group and 50.3 (95%CI: 41.9 - 58.2) in the chemotherapy group Progression free survival was significantly longer in the pembrolizumab group than in the chemotherapy group (HR for disease progression or death, 0.5; 95%CI: 0.37 - 0.68, p < 0.001) At this time, 108 deaths were reported The estimated percentage of patients who were alive at months was 80.2% (95%CI: 72.9 - 85.7) in the pembrolizumab group and 72.4% (95%CI: 64.5 - 78.9) in the chemotherapy group; median overall survival was not reached in either group Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group (hazard ratio for death, 0.60; 95%CI: 0.41 - 0.89; p = 0.005) The objective response rate, assessed according to RECIST, was 44.8% (95%CI: 36.8 - 53.0) in the pembrolizumab group and 27.8% (95%CI: 20.8 - 35.7) in the chemotherapy group The median time to response was 2.2 months in both groups Keytruda combined pemetrexed and platinum using for patients with advanced stage nonsquamous NSCLC without EGFR/ALK aberrations had been demonstrated improvement in OS (HR 0.49, 95%CI: 0.38 - 0.64, p < 0.00001); PFS (HR 0.52, 95%CI: 0.43 - 0.64, p < 0.00001) and a half decreasing risk of death compared to chemotherapy group This results were observed in KEYNOTE 189 clinical trial [8] Journal of military pharmaco-medicine no8-2019 KEYNOTE 407 is a randomized, double-blind, multicenter, placebo-controlled study The criteria for this study were metastatic squamous NSCLC, regardless of tumor PD-L1 expression status and no prior systemic treatment for metastatic disease Keytruda in combination with chemotherapy (carboplatin and either paclitaxel or nab-paclitaxel) significantly improved overall survival, reducing the risk of death by 36% compared to chemotherapy alone (HR = 0.64; 95%CI: 0.49 - 0.85; p = 0.0017) This results are the basis for FDA approval of keytruda in first step treatment in combination with carboplatin and paclitaxel/nab-paclitaxel for patients with advanced squamous NSCLC regardless of tumor PD-L1 expression status [9] KEYNOTE 021 was conducted on 123 previously untreated patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations and irrespective of PD-L1 expression In this trial, keytruda + pem/carbo demonstrated an objective response rate (ORR) that was nearly double the ORR of pem/carbo alone (55% [95%CI: 42 - 68] compared to 29% [95%CI: 18 - 41], respectively; all responses were partial responses) In addition, median PFS in patient treated with keytruda + pem/carbo is 13 months compared to 8.9 months in patients with pem/carbo alone Patients in the keytruda combination arm received keytruda 200 mg, pemetrexed 500 mg/m2 and carboplatin AUC mg/mL/min every three weeks for four cycles followed by keytruda every three weeks [10] INDICATIONS OF PEMBROLIZUMAB (KEYTRUDA) FOR NSCLC From the first approval on October 2nd 2015, FDA has updated times of keytruda indications for NSCLC patients, including: - To treat patients with advanced (metastatic) NSCLC whose disease has progressed after other treatment and with tumors that express a protein called PD-L1 - To treat patients with metastatic NSCLC (as the first line treatment) whose tumors have high PD-L1 expression (tumor proportion score-TPS-of 50% or more) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberration - To treat patients with stage III NSCLC (as monotherapy for the first step treatment) who are not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC and whose tumors express PD-L1 ≥ 1% with no EGFR or ALK genomic tumor aberration - To treat as monotherapy for the second step or greater treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥ 1%) with disease progression on or after platinumcontaining chemotherapy Patients with EGFR or ALK genomic tumor aberration should have disease progression on FDAapproved therapy for these aberration prior to receiving keytruda - To treat in combination with pemetrexed and platinum chemotherapy for the first line treatment of patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberration, irrespective of PD-L1 expression 223 Journal of military pharmaco-medicine no8-2019 - To treat in combination with carboplatin and either paclitaxel or nab-paclitaxel for the first line treatment of patients with metastatic squamous NSCLC regardless of tumor PD-L1 expression status CONCLUSION Pembrolizumab (keytruda) is a monoclonal antibody against PD-L1 and a potential immuno-therapy for NSCLC patients It has been demonstrated effectively with improvement of OS, PFS and mortality REFERENCES Latchman Y et al PD-L2 is a second ligand for PD-1 and inhibits T cell activation Nat Immunol 2001, (3), pp.261-268 Youngnak P et al Differential binding properties of B7-H1 and B7-DC to programmed death-1 Biochem Biophys Res Commun 2003, 307 (3), pp.672-677 Teixido et al PD-L1 expression testing in non-small cell lung cancer Ther Adv Med Oncol 2018, 10, p.1758835918763493 Herbst R.S et al Pembrolizumab versus docetaxel for previously treated, PD-L1positive, advanced non-small cell lung cancer 224 (KEYNOTE-010): A randomised controlled trial Lancet 2016, 387(10027), pp.1540-1550 https://www.fda.gov/drugs/resourcesinformation-approved-drugs/pembrolizumabkeytruda-checkpoint-inhibitor Pembrolizumab (KEYTRUDA) Checkpoint Inhibitor 2016 Mok T.S.K et al Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small cell lung cancer (KEYNOTE-042): A randomized, open-label, controlled, phase trial Lancet, 2019 Reck M et al Pembrolizumab versus chemotherapy for PD-L1-positive non-small cell lung cancer N Engl J Med 2016, 375 (19), pp.1823-1833 Gandhi L et al Pembrolizumab plus chemotherapy in metastatic non-small cell lung cancer N Engl J Med 2018, 378 (22), pp.2078-2092 https://www.fda.gov/drugs/fda-approvespembrolizumab-combination-chemotherapyfirst-line-treatment-metastatic-squamous-nsclc FDA approves pembrolizumab in combination with chemotherapy for first-line treatment of metastatic squamous NSCLC 2018 10 https://www.fda.gov/drugs/resourcesinformation-approved-drugs/pembrolizumabkeytruda-5-10-2017 Pembrolizumab (keytruda) 2017, 5,10 ... resulting in an inactivated status of T cell or inhibited T cells PD-1 also inhibits T cell activity by reducing the activating signal of the CD28 receptor, inhibiting the activity of the CD28... checkpoint In normal conditions, the receptor of immune check point has the function of limiting the activity of T cell, preventing the destruction of normal cells, creating balance Mechanism of pembrolizumab. .. Mechanism of “escaping” the control of immune system of the tumor cells: The immune system plays an important dual role in cancer through the process of immune repair Both the innate and adaptive immune