Merck Receives Complete Response Letter from FDA for KEYTRUDA in High-Risk Early-Stage Triple-Negative Breast Cancer
Mar 30, 2021 23:10
CST Updated
23:10
MSD
Pharmaceutical R&D and Manufacturer
FDA
U.S. Food and Drug Administration
March 30, 2021 /BioValleyBIOON/ -- Merck & Co. recently announced that the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) regarding the supplemental Biologics License Application (sBLA) for the anti-PD-1 therapy Keytruda (brand name: Keytruda; generic name: pembrolizumab). The sBLA sought approval of Keytruda for the treatment of high-risk early-stage triple-negativeBreast Cancer(TNBC) patients, specifically: using Keytruda in combination with chemotherapy for neoadjuvant (preoperative) treatment, followed by using Keytruda as a single agent for adjuvant (postoperative) treatment. TNBC is a difficult-to-treat malignantTumor, approximately 15-20% of breast cancer patients areDiagnosisTNBC.
Currently, MSD is reviewing this CRL and will discuss next steps with the FDA. Notably, in February of this year,FDATumorOncologic Drugs Advisory Committee (ODAC) Meeting ConvenedMeeting, with a vote of 10 in favor and 0 against, it was determined that the review decision on the sBLA should be postponed until further data from the Phase 3 KEYNOTE-522 study are available. The study met one of the dual primary endpoints, namely the pathological complete response rate (pCR), and is currently continuing to evaluate event-free survival (EFS).
The Oncologic Drugs Advisory Committee (ODAC) provides independent expert opinions and recommendations to the FDA regarding marketed and investigational drugs for the treatment of cancer. Although the FDA is not bound by the advisory committee’s guidance, it typically considers its recommendations. The issuance of this Complete Response Letter (CRL) indicates thatFDAComplied with the advisory committee's recommendations.
July 2020,FDAAccepted two sBLAs for Keytruda in the treatment of TNBC. One of the sBLAs received priority review and was granted accelerated approval in November 2020: Keytruda in combination with chemotherapy for the treatment ofTumorPatients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) expressing PD-L1 (Combined Positive Score [CPS] ≥ 10). Notably, this approval marks the first approval of Keytruda in the field of breast cancer.
Another sBLA, namely the one mentioned above that received a CRL, underwent standard review: for the use of Keytruda in patients with high-risk early-stage TNBC. This sBLA is based on data from the Phase 3 KEYNOTE-522 study, whose next interim analysis is calendar-driven, with data expected to be released in the third quarter of 2021.
It should be noted that this CRL does not affect any currently approved indications for Keytruda, including the aforementioned approved indication: Keytruda in combination with chemotherapy for the treatment ofTumorPatients with locally recurrent unresectable or metastatic TNBC expressing PD-L1 (CPS ≥ 10).
KEYNOTE-522 is a randomized, double-blind trial conducted in patients with high-risk early-stage triple-negative breast cancer (TNBC) to evaluate the use of Keytruda plus chemotherapy versus placebo plus chemotherapy as neoadjuvant treatment, followed by Keytruda or placebo as adjuvant therapy.
Data showed that during the neoadjuvant treatment period, regardless of PD-L1 expression status, Keytruda plus chemotherapy (n=401) demonstrated a statistically significant increase in pathological complete response (pCR) compared with chemotherapy alone (n=201) (pCR: 64.8% vs. 51.2%, p=0.00055). For the other primary endpoint, event-free survival (EFS), with a median follow-up of 15.5 months, the Keytruda regimen showed a favorable trend compared with the chemotherapy–placebo regimen, reducing the risk of disease progression during the neoadjuvant phase and recurrence during the adjuvant phase by 37% (HR=0.63 [95% CI: 0.43–0.93]).
Notably, based on the study 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. Previously,FDABreakthrough Therapy Designation (BTD) Granted to Keytruda Plus Chemotherapy for Neoadjuvant Treatment in Patients with High-Risk Early-Stage Triple-Negative Breast Cancer (TNBC)
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, 10 anti-PD-(L)1 therapies have been approved for market launch, with Keytruda emerging as the leader. Its global sales reached $14.38 billion in 2020, representing a 30% year-on-year increase.
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 specifically defined by the negative expression of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2). This aggressive form of breast cancer progresses rapidly, carries a 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.
In terms of new drugs for TNBC, in March 2019, the United StatesFDAApproval granted for Roche’s anti-PD-L1 therapy Tecentriq (atezolizumab) in combination with chemotherapy (Abraxane) as 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 regimen as the first cancer immunotherapy for the treatment of PD-L1-positive metastatic TNBC. In the Phase III IMpassion130 study, compared with placebo plus Abraxane, 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 7-month improvement 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’ antibody-drug conjugate (ADC) Trodelvy (sacituzumab govitecan-hziy) for adult patients with metastatic triple-negative breast cancer (mTNBC) who had previously received at least two prior therapies for metastatic disease. Notably, Trodelvy is the first 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 Merck’s anti-PD-1 therapy Keytruda, in combination with chemotherapy, for the treatment of 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. Results showed that inTumorIn 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)