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Triple Negative Breast Cancer (TNBC) Immunotherapy: Merck’s Keytruda
Triple Negative Breast Cancer (TNBC) Immunotherapy: Merck’s Keytruda. Triple Negative Breast Cancer (TNBC) Immunotherapy! Merck’s Keytruda in the treatment of high-risk early stage TNBC phase 3 clinical: significantly prolongs event-free survival!
Merck & Co recently announced the anti-PD-1 therapy Keytruda (generic name: pembrolizumab, pembrolizumab) for the treatment of high-risk early triple negative Positive event-free survival (EFS) data from the critical neoadjuvant/adjuvant phase 3 KEYNOTE-522 study of breast cancer (TNBC). The trial investigated the Keytruda regimen (Keytruda + chemotherapy for neoadjuvant [preoperative] treatment, Keytruda as a monotherapy for adjuvant [postoperative] treatment), and combined with the chemotherapy-placebo regimen (placebo + chemotherapy for neoadjuvant [Preoperative] treatment and placebo for auxiliary [postoperative] treatment) were compared.
Previously published data showed that the trial reached the common primary endpoint of pathological complete remission (pCR): in the neoadjuvant treatment phase, regardless of the PD-L1 expression status, compared with chemotherapy (n=201), Keytruda + chemotherapy (n =401) showed a statistically significant increase in pCR (pCR: 64.8% vs 51.2%, p=0.00055). Based on this data, Keytruda is the first anti-PD-1 therapy to show a statistically significant improvement in pCR as a neoadjuvant therapy for TNBC (regardless of PD-L1 status). At the same time, based on this data, the FDA has granted Keytruda+ chemotherapy a breakthrough drug qualification (BTD) for neoadjuvant treatment of high-risk early TNBC patients.
The latest data released this time show that the trial has also reached the common primary endpoint of event-free survival (EFS): according to the analysis conducted by the Independent Data Monitoring Committee (DMC), it is combined with the chemotherapy-placebo regimen (placebo + chemotherapy for new Compared with adjuvant therapy and placebo for adjuvant therapy, the Keytruda regimen (Keytruda + chemotherapy for neoadjuvant therapy, Keytruda for adjuvant therapy) has statistically significant and clinically significant improvements in EFS. Based on this data, Keytruda is the first anti-PD-1 therapy to show statistically significant improvement in EFS as a neoadjuvant and adjuvant therapy for TNBC.
The specific data are: a median follow-up of 39 months. Compared with the chemotherapy-placebo regimen, the Keytruda regimen significantly reduced the risk of EFS events by 37% (HR=0.63; 95%CI: 0.48-0.82; p=0.00031). It is a statistically significant and clinically significant EFS result. EFS is defined as the time from randomization to the first occurrence of disease progression (excluding radical surgery), local/distal recurrence, second primary cancer, or death from any cause. The pre-designated exploratory subgroup EFS analysis showed that the EFS benefit of the Keytruda regimen was independent of PD-L1 expression status: (1) In the PD-L1 positive subgroup (CPS≥1, n=973), compared with chemotherapy-placebo Compared with the regimen, the risk of EFS events was reduced by 33% (HR=0.67); (2) In the PD-L1 negative subgroup (CPS<1, n=197), the risk of EFS events was reduced compared with the chemotherapy-placebo regimen 52% (HR=0.48).
The trial continued with additional follow-up for overall survival (OS), which is a key secondary endpoint. In the fourth interim analysis, although these data did not exceed the limits of statistical significance, the Keytruda regimen reduced the risk of death by 28% compared with the chemotherapy-placebo regimen (HR=0.72; 95%CI0.51-1.02 ; P=0.03214). The safety of the Keytruda program is consistent with the known safety of each drug in the program, and no new safety issues have been discovered.
In view of the high recurrence rate in the first 5 years after diagnosis, high-risk early TNBC patients need new treatment options. The results of the KEYNOTE-522 study confirmed the potential of Keytruda’s neoadjuvant and adjuvant programs for early treatment of such patients. Vicki Goodman, vice president of clinical research at Merck Research Laboratories, said: “These highly anticipated TNBC population event-free survival (EFS) results are based on the early findings of the KEYNOTE-522 trial, and further support the potential of Keytruda in these patients. Application. KEYNOTE-522 is the first large-scale randomized phase 3 study that reports statistically significant and clinically significant EFS results in phase II and phase III TNBC patients. We have submitted these data to the US FDA and are currently under supervision Work closely with the FDA on the review.”
As mentioned earlier, Merck received a complete response letter (CRL) from the US FDA in March 2021, involving a supplementary biologics license application (sBLA) from Keytruda, which is based on the pCR data of the KEYNOTE-522 trial and For early interim EFS results, application for approval of Keytruda for the treatment of high-risk early TNBC patients, specifically: Keytruda combined with chemotherapy for neoadjuvant (preoperative) treatment, and then Keytruda as a single drug for adjuvant (postoperative) treatment. The FDA’s CRL was issued after the FDA Oncology Drug Advisory Committee (ODAC) meeting in February this year. With 10 votes in favor and 0 votes against, the meeting concluded that the review decision of sBLA should be postponed until the KEYNOTE-522 trial provides more The data.
TNBC is a difficult-to-treat malignant tumor. About 15-20% of breast cancer patients are diagnosed with TNBC. In November 2020, the FDA accelerated the approval of the Keytruda combined chemotherapy regimen for the treatment of locally recurrent unresectable or metastatic TNBC patients whose tumors express PD-L1 (combined with a positive score [CPS] ≥ 10). This approval marks the first approval of Keytruda in the field of breast cancer.
It should be pointed out that the CRL from the FDA does not affect any currently approved Keytruda indications, including the above approved: Keytruda combined with chemotherapy for the treatment of tumors expressing PD-L1 (CPS ≥ 10) for locally recurring unresectable or metastatic disease TNBC patients. The Keytruda TNBC clinical development project includes some internal research and external collaborative trials, including the ongoing research KEYNOTE-242 and KEYNOTE-355.
Keytruda belongs to anti-PD-(L)1 tumor immunotherapy. This type of therapy helps detect and fight tumor cells by improving the ability of the human immune system. Keytruda is an anti-PD-1 therapy that blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2, thereby activating T lymphocytes that may affect tumor cells and healthy cells. At present, Keytruda has become the basic therapy for many types of cancer.
Globally, 10 anti-PD-(L)1 therapies have been approved for marketing. Keytruda is the leader among them. In 2020, global sales reached 14.38 billion U.S. dollars, an increase of 30% over the previous year. Earlier, the pharmaceutical market research organization EvaluatePharma released a report predicting that Keytruda’s sales in 2026 will reach 24.91 billion US dollars, becoming the world’s best-selling drug. And Bristol-Myers Squibb’s anti-PD-1 therapy Opdivo (Odivo, Navulimab) sales will also reach 12.677 billion US dollars, becoming the world’s second best-selling drug.
Breast cancer is the most common type of cancer among women, with more than 2 million cases diagnosed globally each year. TNBC accounts for about 15-20% of all breast cancers. Compared with other types of breast cancer, TNBC is more common in women under the age of 50. TNBC specifically refers to breast cancer with negative expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2), which is an aggressive breast cancer. The progress is rapid, the prognosis is extremely poor, the recurrence rate is high, and the 5-year survival rate is less than 15%. TNBC is ineffective against hormone therapy and HER2 targeted therapy (such as Herceptin), and clinical treatment options are very limited, mainly relying on chemotherapy. Metastatic TNBC is one of the most aggressive and difficult to treat breast cancers.
In terms of new TNBC drugs, in March 2019, the US FDA approved Roche’s anti-PD-L1 therapy Tecentriq (teshanqi, generic name: atezolizumab, atezolizumab) combined with chemotherapy (Abraxane) for the first-line treatment of PD-L1-positive unresectable local Patients with advanced or metastatic TNBC. This approval makes the Tecentriq+Abraxane combination the first cancer immunotherapy regimen for the treatment of PD-L1-positive metastatic TNBC.
In April 2020, the US FDA approved Immunomedics’ antibody drug conjugate (ADC) Trodelvy (sacituzumab govitecan-hziy) for use in metastatic triple-negative breast cancer (mTNBC) that has previously received at least two therapies for the treatment of metastatic disease Adult patients. It is worth mentioning that Trodelvy is the first ADC drug approved by the FDA to treat relapsed or refractory mTNBC, and it is also the first anti-Trop-2 ADC drug approved by the FDA.
In November 2020, the US FDA approved Merck’s anti-PD-1 therapy Keytruda, combined with chemotherapy to treat locally recurrent unresectable or metastatic TNBC patients whose tumors express PD-L1 (combined with a positive score [CPS] ≥ 10).
(source:internet, reference only)