NSCLC is the most common type of lung cancer. About 85% of lung cancers are non-small cell lung cancer. Squamous cell carcinoma, adenocarcinoma and large cell carcinoma are all subtypes of non-small cell lung cancer. KRAS mutations are present in approximately 20% to 30% of lung adenocarcinoma patients, and KRAS is one of the most common recurrent oncogene mutations in lung cancer. Breast cancer is the most common cancer among women worldwide. It is also the leading cause of cancer deaths in women (~450,000/year). Metastatic breast cancer (mBC) occurs when cancer has spread beyond the breast to other parts of the body. In addition to patients initially diagnosed with mBC, almost 30% of women diagnosed with early breast cancer will eventually develop mBC. Patients diagnosed with mBC face a median survival period of 2-4 years, and mBC is still incurable. Pembrolizumab is a humanized IgG4 monoclonal antibody against programmed death receptor-1 (PD-1). Pembrolizumab and methods of preparing and using the compound are disclosed in WO2008156712. Pembrolizumab has been shown to inhibit the binding of PD-1 to PD-L1 and PD-L2, and has been tested in multiple clinical trials. Pembrolizumab is approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic melanoma whose tumors have high PD-L1 expression and as determined by FDA-approved tests Metastatic NSCLC patients without EGFR or ALK genomic tumor aberrations and no previous systemic chemotherapy treatment, metastatic NSCLC patients whose tumors express PD-L1 and have disease progression during or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression when receiving FDA-approved therapies for these aberrations before receiving pembrolizumab. Pembrolizumab is also approved for use in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) who have disease progression when or after platinum-containing chemotherapy and for patients with refractory typical Hodgkin's lymph Tumors or adult and pediatric patients who relapse after 3 or more prior lines of therapy.

Lambrolizumab Indications

1. Melanoma that cannot be removed or metastasized.
2. First-line treatment of metastatic NSCLC with high expression of NSCLC PD-L1 without EGFR or ALK gene mutation; metastatic NSCLC with high expression of PD-L1 after platinum-containing regimen or first-line treatment with EGFR or ALK mutation; combined training of metastatic NSCLC Metraxecarboplatin is used as first-line treatment.
3. Head and neck squamous cell carcinoma that recurred or metastasized after platinum-containing chemotherapy.
4. Patients after the third-line treatment of classic Hodgkin's lymphoma.
5. Patients with primary mediastinal large B cell lymphatic progression after second-line treatment.
6. Bladder epithelial cancer.
7. Microsatellite unstable and highly malignant tumors.
8. Gastric cancer.
9. Cervical cancer.

Lambrolizumab Dosage

200mg intravenous drip, once every 3 weeks Precautions Skin toxicity, diabetes, gastrointestinal toxicity, liver toxicity, hypersensitivity, hypophysitis, injection reaction
Be careful when using it in response to kidney toxicity, lung toxicity, and thyroid disease.

Lambrolizumab Clinical application

1.The clinical application of pembrolizumab in the treatment of NSCLC 1) Single agent for second-line treatment of PD-L1-positive metastatic NSCLC with disease progression after platinum therapy Among them, patients with ERFG or ALK gene mutations should use KEYNOTE-001 after targeted therapy. This is the first phase I clinical study initiated. The trial included 495 patients with advanced NSCLC who received pembrolizumab 2 mg·kg or 10 mg·kg for a 3-week program and 10 mg·kg for a 2-week program. The study found that pembrolizumab objective response rate (objective response, ORR) was 19.4%, effective duration was 12.5 months, median progression-free survival (PFS) was 3.7 months, median overall survival (overallsurvival, OS) is 12 months. Subgroup analysis showed that the effective rates of 394 treated patients and 101 newly treated patients were 18% and 25%, the median effective duration was 10 months and 23 months, and the median OS was 9.3 months. And 16 months. In addition, the test also found that the effective rate of the PD-L1 high expression (≥50%) group was 45%, and the median effective duration was 12.5 months, which was better than the PD-L1 low expression group. The analysis found that in patients who had received radiotherapy, PFS and OS were higher than those who had not received radiotherapy (PFS was 4.4 months vs 2.1 months, respectively, OS was 10.7 months vs 5.3 months). Studies have found that the treatment of pembrolizumab is well tolerated, and common adverse reactions are fatigue, itching and loss of appetite. The incidence of treatment-related adverse reactions of grade 3 and above was 10%. Pneumonia occurred in 18 patients (3.6%), including 9 patients (1.8%) with grade 3 or higher pneumonia, and 1 case died.

2.Single agent for the first-line treatment of metastatic NSCLC with high PD-L1 expression (≥50%) and no EGFR or ALK gene mutation

KEYNOTE-024 is a phase III clinical trial designed to evaluate the effectiveness and safety of pembrolizumab (200 mg fixed dose) as a first-line treatment for NSCLC. A total of 305 patients were enrolled in the study, and the enrollment requirements were newly-treated NSCLC patients with PD-L1 expression ≥50% and no EGFR gene mutation or ALK gene rearrangement. The results showed that compared with the standard platinum two-drug chemotherapy regimen, the median PFS of the pembrolizumab group was longer than that of the chemotherapy group by 4.3 months, and the PFS of the two groups were 10.3 months and 6.0 months, respectively; pembrolizumab The OS of the group was longer than that of the chemotherapy group, and the expected 6-month overall survival rates were 80.2% and 72.4%, respectively; the ORR of the pembrolizumab group was higher than that of the chemotherapy group, 44.8% and 27.8%, respectively. In terms of safety, the incidence of treatment-related adverse events in the pembrolizumab group was lower than that in the chemotherapy group (73.4% and 90.0%, respectively). The incidence of adverse events above grade 3 in the pembrolizumab group was 26.6% and that of the chemotherapy group was 53.3 %. KEYNOTE-024 verifies for the first time that pembrolizumab is superior to standard platinum-containing dual-drug regimen in the first-line treatment of NSCLC with high PD-L1 expression. Based on the results of this study, pembrolizumab is recommended for the first-line treatment of PD-L1 positive (≥50%) advanced NSCLC.

3、Combination of carboplatin and pemetrexed for the first-line treatment of metastatic non-squamous NSCLC

KEYNOTE-021 is a phase II cohort study to evaluate whether pembrolizumab combined with platinum-containing dual-agent chemotherapy can improve the efficacy of advanced non-squamous NSCLC patients. The study was conducted in 26 centers in the United States and Taiwan, China, and included a total of 123 patients. Enrollment requirements are non-squamous patients with stage IIIB or IV who have not received chemotherapy before Patients with NSCLC without EGFR or ALK gene mutations. The results of the study showed that the ORR of the primary endpoint of the pembrolizumab (200mg) combined chemotherapy group was better than that of the chemotherapy alone group, 55% and 29%, respectively, P=0.0016. According to the stratification of PD-L1 expression level, patients with PD-L1 expression ≥50%, the ORR of pembrolizumab combined with chemotherapy is better than those with PD-L1 expression <1% and 1%~49%, respectively 80 %, 57%, and 26%, while the ORR of the chemotherapy-only group was 35%, 13%, and 39%, respectively. The PFS of the combined treatment group was 13 months, which was significantly better than the chemotherapy group (8.9 months). There was no significant difference in OS between the combination treatment group and the chemotherapy group. In terms of safety, compared with the chemotherapy group, the incidence of treatment-related adverse events above grade 3 was similar in the combined treatment group, 39% and 26%, respectively. The most common adverse events of grade 3 or higher in the pembrolizumab combined chemotherapy group were anemia (12%) and neutrophil decline (5%), and another 3% of patients had acute kidney injury, decreased lymphocyte count, and fatigue , Neutropenia, infection and thrombocytopenia. The most common adverse events above grade 3 in the chemotherapy group were anemia (15%) and neutropenia, pancytopenia and thrombocytopenia (3%). In the combination therapy group, 1 patient (2%)
Died due to sepsis; in the chemotherapy group, 2 patients (3%) died of sepsis and pancytopenia. KEYNOTE-021 prospectively evaluated the effectiveness of PD-1 inhibitors combined with platinum two-drug chemotherapy in NSCLC patients for the first time.
1) First-line treatment for patients with advanced NSCLC who are PD-L1 positive (>1%) and have no EGFR or ALK gene mutations. KEYNOTE-042 is a phase 3 clinical trial that aims to study the overall survival rate of pembrolizumab and platinum-containing chemotherapy in patients with PD-L1 positive (>1%) newly-treated advanced NSCLC. The entry condition is PD-L1 positive
2)Patients with advanced NSCLC who have sex (>1%) and have no EGFR or ALK gene mutations. The pembrolizumab group used a fixed dose of 200 mg once every 3 weeks; the control group was a chemotherapy regimen of carboplatin + paclitaxel or carboplatin + pemetrexed. The primary study endpoint was OS, and the secondary endpoint was PFS and ORR. The study started on October 30, 2014, and 1445 patients have been recruited.
3)Postoperative adjuvant treatment for patients with early NSCLC. KEYNOTE-091 is a phase 3 clinical trial conducted in patients with stage IB/II-IIIA NSCLC. The purpose is to study whether pembrolizumab can improve DFS in early stage NSCLC patients after surgery. The experimental group used pembrolizumab 200 mg, a 3-week program, and the control group was a placebo. The primary endpoint was DFS, and the secondary endpoint was OS and lung cancer-specific survival (LCSS). The study began in November 2015, and it is expected to recruit 1,380 patients. Currently, the trial is ongoing.
4)Pembrolizumab combined with chemotherapy is used for the first-line treatment of squamous NSCLC. KEYNOTE-407 is a randomized, double-blind phase 3 clinical study to evaluate the effectiveness of pembrolizumab combined with carboplatin + paclitaxel/albumin paclitaxel in the first-line treatment of metastatic squamous NSCLC. The primary study endpoint is PFS and OS, and the secondary endpoint is ORR. The study started in June 2016 and is expected to recruit 560 patients and is currently ongoing.
5) Pembrolizumab is the second-line treatment in two groups of patients with advanced NSCLC with PD-L1 expression of 1%~49% and ≥50%. NCT02864394 is a phase 3 clinical trial that aims to evaluate the effectiveness of pembrolizumab and docetaxel in second-line treatment in NSCLC that has progressed after platinum-containing chemotherapy with positive PD-L1 expression. The experimental group was pembrolizumab 2mg·kg, 3 weeks plan; the control group was docetaxel 75mg·m, 3 weeks plan. The main research endpoint is PD-L1 expression 1%~49% and ≥50% of OS and PFS in the two groups of patients, secondary endpoints are duration of remission (DOR), ORR, and adverse events. The study started in September 2016 and is expected to recruit 740 patients.