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KEYNOTE Drug Study for Head and neck squamous cell carcinoma
KEYNOTE Drug Study for Head and neck squamous cell carcinoma. Head and neck squamous cell carcinoma (HNSCC) is one of the common malignant tumors. In recent years, with the development of surgery and radiotherapy technology, chemotherapy and EGFR-targeted monoclonal antibody therapy have been included in the treatment of locally advanced HNSCC, but more than half of the patients still end up Recurrence or distant metastasis has occurred, and the emergence of immunotherapy undoubtedly provides a better treatment option for recurrent and metastatic head and neck squamous cell carcinoma (r/mHNSCC).
KEYNOTE-012-Pembrolizumab r/mHNSCC curative effect preliminary study
KEYNOTE-012 is a basket test that contains multiple tumor types. Efficacy data from the r/mHNSCC cohort showed that the response rate of treatment with pembrolizumab (10 mg/kg, Q2w) was as high as 20%. On this basis, the researchers carried out a larger KEYNOTE -012 extended cohort study . The extended cohort does not consider the expression of PD-L1 and the presence of HPV, the drug dose is changed to 200 mg iv Q3w, and imaging evaluation is performed every 8 weeks. The primary study endpoint is the overall response rate (ORR).
The study included 132 patients with r/mHNSCC. 56.8% of recurrent patients received ≥ second-line treatment. According to the RECIST 1.1 standard, the ORR was 18.2% (95% CI, 11.1-27.2), and 31.3% of patients were in stable condition. The most common adverse drug events included fatigue (12.1%), loss of appetite (6.8%), fever (6.1%) and skin rash (5.3%).
In August 2016, the U.S. Food and Drug Administration (FDA) accelerated the approval of pembrolizumab for r/mHNSCC patients whose disease progressed during or after platinum-containing chemotherapy treatment. More importantly, HNSCC patients do not need to detect the expression status of tumor PD-L1 before receiving this regimen.
The twists and turns of KEYNOTE-040
The purpose of the phase III KEYNOTE-040 study is to verify the effectiveness of pembrolizumab against three standard chemotherapy (methotrexate, docetaxel or cetuximab). The research was carried out in 97 centers in 20 countries. A total of 495 patients were enrolled.
Interim analysis showed that the median overall survival (mOS) of the two groups was 8.4 months and 6.9 months (HR 0.82), respectively. Although the P value was statistically different (P = 0.03), it did not reach the preset study endpoint . Despite this, the FDA has not withdrawn the indication for pembrolizumab. An 18% reduction in the risk of death is still clinically significant.
In 2018, “The Lancet” published the latest results of the KEYNOTE-040 study . The 1-year survival rates in the two groups were 37% and 26.5%, respectively. The median duration of response (DoR) in the experimental group was 18.4 months, while the control group was only 5 months. The 2019 CSCO Head and Neck Tumor Diagnosis and Treatment Guidelines recommend pembrolizumab as a second-line/rescue treatment (Class 1A evidence).
KEYNOTE-048- Redefine the gold standard for r/m HNSCC first-line treatment
The results of the KEYNOTE-048 test were announced at the 2019 ASCO conference. Subsequently, the FDA approved pembrolizumab as a single agent for PD-L1 CPS ≥ 1 and combined platinum + fluorouracil (FU) for first-line treatment of r/m HNSCC. One PD-1 inhibitor was approved for the first-line treatment of advanced HNSCC.
In December 2020, NMPA approved pembrolizumab for the first-line treatment of r/m HNSCC patients whose tumors express PD-L1 (comprehensive positive score (CPS) ≥ 20) through a fully validated test, becoming the first domestic PD-1 inhibitor for the first-line treatment of HNSCC.
KEYNOTE-048 is a randomized, open-label phase three study, enrolling a total of 882 newly-treated r/m HNSCC patients, who were randomly assigned to the pembrolizumab single-agent group (P group, 301). For example, pembrolizumab 200 mgQ3W, 35 cycles in total), pembrolizumab combined with chemotherapy group (P+C group, 281 cases, pembrolizumab 200 mgQ3W, 35 cycles + 6 cycles of chemotherapy (cisplatin 100) mg/m2 or carboplatin AUC5Q3W+5-Fu1000 mg/m2/d, 4dQ3W)), or chemotherapy combined with cetuximab group (group E, 300 cases, cetuximab 250 mg/㎡Q1W+6 cycles of chemotherapy ). To compare the efficacy of pembrolizumab or pembrolizumab combined with chemotherapy and first-line standard treatment (group E, cetuximab combined with chemotherapy). The primary study endpoint is OS.
The latest results published at the ESMO Conference in 2020 show that , for patients with CPS ≥ 20, the median OS of group P is better than that of group E (14.8:10.7 months) (HR 0.58); the 4-year OS rate was 21.6% vs 8.0 %, DoR exceeds Group E by 5 times (23.4 months vs 4.2 months). Compared with group E, the P+C treatment regimen improved OS in all populations: mOS of P+C group was 13.0 months, while group E was 10.7 months (HR 0.71), and the 4-year OS rate was 19.4% vs. 4.5%. Among all patients, pembrolizumab has a significant decrease in the incidence of adverse reactions compared with standard treatment (58.3% vs 96.9%), and the incidence of adverse reactions above grade 3 is 17.0% vs 69.3%.
Immunotherapy can make the tumor of some patients get continuous remission, and the incidence of drug resistance in immunotherapy is relatively low, so patients will have a long period of tumor remission, thereby prolonging OS.
(source:internet, reference only)