Merck's Keytruda Achieves Dual Primary Endpoints in Phase 3 KEYNOTE-522 Trial for High-Risk Early-Stage Triple-Negative Breast Cancer

May 14, 2021 /BioValleyBIOON/ -- Merck & Co. recently announced the results of Keytruda (Keytruda, generic name: pembrolizumab), an anti-PD-1 therapy, for the treatment of high-risk early-stage triple-negativeBreast CancerPositive results from the key phase 3 KEYNOTE-522 study in triple-negative breast cancer (TNBC). The trial evaluated preoperative (neoadjuvant) treatment with Keytruda plus chemotherapy versus placebo plus chemotherapy, followed by postoperative (adjuvant) treatment with Keytruda versus placebo.

Previously announced data showed that the trial met its co-primary endpoint of pathological complete response (pCR): during the neoadjuvant treatment period, Keytruda plus chemotherapy (n=401) demonstrated a statistically significant increase in pCR compared with chemotherapy alone (n=201), regardless of PD-L1 expression status (pCR: 64.8% vs. 51.2%; p=0.00055). Based on these data,Keytruda is the first anti-PD-1 therapy to demonstrate a statistically significant improvement in pathological complete response (pCR) as neoadjuvant treatment for triple-negative breast cancer (TNBC), regardless of PD-L1 status.Meanwhile, based on this data,FDABreakthrough Therapy Designation (BTD) Granted for Keytruda Plus Chemotherapy as Neoadjuvant Treatment for Patients with High-Risk Early-Stage Triple-Negative Breast Cancer (TNBC)

The latest data released indicate that the trial also met the co-primary endpoint of event-free survival (EFS): according to an interim analysis conducted by the independent data monitoring committee (DMC), the Keytruda regimen (Keytruda plus chemotherapy for neoadjuvant treatment, followed by Keytruda for adjuvant treatment) demonstrated a statistically and clinically significant improvement in EFS compared with the chemotherapy–placebo regimen (placebo plus chemotherapy for neoadjuvant treatment, followed by placebo for adjuvant treatment). Based on these data,Keytruda is the first anti-PD-1 therapy to demonstrate a statistically significant improvement in event-free survival (EFS) in the neoadjuvant and adjuvant treatment of triple-negative breast cancer (TNBC).

In this trial, the safety profile of Keytruda was consistent with previously reported data, and no new safety signals were identified.

Dr. Roy Baynes, Chief Medical Officer, Senior Vice President, and Head of Global Clinical Development at MSD Research Laboratories, stated: “Keytruda is the first immunotherapy to demonstrate positive results in event-free survival (EFS) among patients with high-risk early-stage triple-negative breast cancer (TNBC). The initial improvement in pathological complete response rates observed following neoadjuvant therapy was highly encouraging, and now, with four-year mature data including a statistically significant improvement in EFS, we look forward to working with”FDA“Collaborate with other global regulatory authorities to bring this new option to patients as soon as possible. We thank the study participants, who are essential to our efforts to advance potential treatment options for patients with triple-negative breast cancer (TNBC).”

As previously mentioned, MSD received approval from the U.S. Food and Drug Administration (FDA) in March 2021.FDA) a complete response letter (CRL) regarding a supplemental biologics license application (sBLA) for Keytruda, which sought approval for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) based on pathological complete response (pCR) data from the KEYNOTE-522 trial and earlier interim event-free survival (EFS) results; specifically, the application proposed the use of Keytruda in combination with chemotherapy as neoadjuvant (preoperative) treatment, followed by Keytruda as monotherapy as adjuvant (postoperative) treatment.

The FDA's CRL was issued in February this year.FDATumorOncologic Drugs Advisory Committee (ODAC)ConferenceSubsequently issued, the meeting concluded with a vote of 10 in favor and 0 against that the review decision on the sBLA should be deferred until more data from the KEYNOTE-522 trial become available.

TNBC is a difficult-to-treat malignant tumor, with approximately 15-20% of breast cancer patients beingDiagnosisas TNBC. In November 2020,FDAAccelerated Approval of Keytruda in Combination with Chemotherapy Regimen for the Treatment ofTumorPatients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) expressing PD-L1 (Combined Positive Score [CPS] ≥ 10). This approval marks the first approval of Keytruda in the field of breast cancer.

It should be noted that, fromFDACRL does not affect any currently approved indications for Keytruda, including the aforementioned approved indication: Keytruda in combination with chemotherapyTumorPatients with locally recurrent unresectable or metastatic TNBC expressing PD-L1 (CPS ≥ 10).

The Keytruda TNBC clinical development program includes internal studies and external collaborative trials, including the ongoing KEYNOTE-242 and KEYNOTE-355 studies.

Keytruda belongs to the class of anti-PD-(L)1 tumor immunotherapies, which help detect and combat tumor cells by enhancing the capabilities of the human immune system. Keytruda is an anti-PD-1 therapy that activates potential effects by blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2.TumorT lymphocytes of cells and healthy cells. Currently, Keytruda has become a foundational therapy for multiple types of cancer.

Globally, more than 10 anti-PD-(L)1 therapies have been approved for marketing, with Keytruda emerging as the frontrunner. In 2020, its global sales reached $14.38 billion, representing a 30% increase from the previous year.

Previously, the pharmaceutical market research firm EvaluatePharma released a report predicting that Keytruda’s sales would reach $24.91 billion in 2026, making it the world’s best-selling drug. Meanwhile, Bristol-Myers Squibb’s anti-PD-1 therapy Opdivo (Opdivo, nivolumab) is also projected to achieve sales of $12.677 billion, becoming the second best-selling drug globally.

Breast cancer is the most common type of cancer in women, with over 2 million new cases diagnosed globally each year. Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of all breast cancers and is more prevalent in women under the age of 50 compared to other breast cancer subtypes. TNBC is defined by the negative expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). This aggressive form of breast cancer progresses rapidly, carries a very poor prognosis, has a high recurrence rate, and has a 5-year survival rate of less than 15%. TNBC does not respond to hormonal therapy or HER2-targeted therapies (such as Herceptin), resulting in very limited clinical treatment options that primarily rely on chemotherapy. Metastatic TNBC is among the most aggressive and difficult-to-treat forms of breast cancer.

Regarding new drugs for TNBC, in March 2019, the United StatesFDAApproval of Roche's Anti-PD-L1 TherapyTecentriq (Atezolizumab) in Combination with Chemotherapy (Abraxane)First-line treatment for patients with PD-L1-positive, unresectable locally advanced or metastatic triple-negative breast cancer (TNBC). This approval establishes the Tecentriq plus Abraxane combination as the first cancer immunotherapy regimen for the treatment of PD-L1-positive metastatic TNBC. In the Phase III IMpassion130 study, compared with the placebo plus Abraxane regimen, the Tecentriq plus Abraxane regimen significantly reduced the risk of disease progression or death by 40% in PD-L1-positive patients (median PFS: 7.4 months vs. 4.8 months; HR=0.60; 95% CI: 0.48–0.77; p<0.0001) and demonstrated a clinically meaningful improvement of 7 months in overall survival (OS) (median OS: 25.0 vs. 18.0 months; HR=0.71; 95% CI: 0.54–0.93).

In April 2020, the U.S. FDA approved Immunomedics, Inc.Antibody-Drug Conjugate (ADC) Trodelvy (sacituzumab govitecan-hziy), for adult patients with metastatic triple-negative breast cancer (mTNBC) who have previously received at least two therapies for metastatic disease. Notably, Trodelvy is the first antibody-drug conjugate (ADC) approved by the FDA specifically for the treatment of relapsed or refractory mTNBC, and alsoFDAThe first approved anti-Trop-2 ADC drug. Data from the single-arm, multicenter Phase II IMMU-132-01 study showed that in heavily pretreated adult patients with metastatic triple-negative breast cancer (mTNBC) who had previously received multiple therapies (range: 2–10 regimens) for metastatic disease, Trodelvy treatment achieved an objective response rate (ORR) of 33.3% (95% CI: 24.6, 43.1) and a median duration of response (DOR) of 7.7 months (95% CI: 4.9, 10.8).

November 2020, United StatesFDAApproval of MSD's Anti-PD-1 TherapyKeytruda in Combination with ChemotherapyFor patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (Combined Positive Score [CPS] ≥ 10). This approval is based on data from the Phase 3 KEYNOTE-355 study (NCT02819518). The study was conducted in patients with locally recurrent, unresectable, or metastatic TNBC who had not previously received chemotherapy for metastatic disease. The results showed that inTumorAmong patients expressing PD-L1 with a Combined Positive Score (CPS) ≥10 (accounting for 38% of the study population), the Keytruda plus chemotherapy group demonstrated a statistically significant 35% reduction in the risk of disease progression or death compared to the placebo plus chemotherapy group (HR=0.65; 95% CI: 0.49-0.86; p=0.0012). Progression-free survival (PFS) was significantly prolonged with both statistical and clinical significance (median PFS: 9.7 months vs. 5.6 months). Furthermore, the objective response rate (ORR) was 53% in the Keytruda plus chemotherapy group (complete response rate [CR]: 17%; partial response rate [PR]: 36%), compared to 40% in the placebo plus chemotherapy group (CR: 13%; PR: 27%). The median duration of response (DOR) was 19.3 months in the Keytruda plus chemotherapy group versus 7.3 months in the placebo plus chemotherapy group. In this study, the median duration of treatment with Keytruda was 5.7 months. Per the recommendation of the Independent Data Monitoring Committee (DMC), the study will continue without any modifications to evaluate the other dual primary endpoint, overall survival (OS). (Bioon.com)

Original Source: Merck Announces Phase 3 KEYNOTE-522 Trial Met Dual Primary Endpoint of Event-Free Survival (EFS) in Patients With High-Risk Early-Stage Triple-Negative Breast Cancer (TNBC)