Merck's Keytruda for High-Risk Early-Stage Triple-Negative Breast Cancer Rejected by FDA Advisory Committee

February 14, 2021 /BioValleyBIOON/ -- Merck & Co. recently announced that the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC)MeetingAs a result, the meeting discussed a supplemental Biologics License Application (sBLA) for the anti-PD-1 therapy Keytruda (brand name: Keytruda; generic name: pembrolizumab), 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 Keytruda as a monotherapy for adjuvant (postoperative) treatment. TNBC is a difficult-to-treat malignantTumor, approximately 15-20% of breast cancer patients areDiagnosisfor TNBC.

By a vote of 10 in favor and 0 against, the Committee concluded that the review decision should be deferred until further data from the Phase 3 KEYNOTE-522 study become available. The study met one of its dual primary endpoints, pathological complete response (pCR) rate, and is continuing to evaluate event-free survival (EFS). The Oncologic Drugs Advisory Committee (ODAC) provides independent expert advice and recommendations to the FDA on marketed and investigational drugs for the treatment of cancer.FDANot bound by the committee’s guidance, but will consider its 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 Under Standard Review: Keytruda for Patients with High-Risk Early-Stage TNBCFDAThe Prescription Drug User Fee Act (PDUFA) target date for this sBLA has been set for March 29, 2021. 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 announced in the third quarter of 2021.

Dr. Roy Baynes, Chief Medical Officer, Senior Vice President, and Head of Global Clinical Development at MSD Research Laboratories, stated: “Triple-negative breast cancer (TNBC) is an aggressive disease, and we all agree that patients with early-stage disease need more treatment options. Although we are disappointed with the results presented at today’s meeting, we believe Keytruda can help address the unmet medical needs in these patients. We remain confident in the results of the KEYNOTE-522 trial, including the observed pathological complete response rate and the encouraging interim event-free survival data. We look forward to continuing to work withFDAcollaboration, review our application. We thank all the patients, caregivers, and healthcare providers who participated in this study.”

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 combined with chemotherapy versus placebo combined with chemotherapy as neoadjuvant therapy prior to surgery, followed by adjuvant therapy with Keytruda or placebo after surgery.

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 a neoadjuvant treatment for triple-negative breast cancer (TNBC), regardless of PD-L1 status. Previously,FDABreakthrough Therapy Designation (BTD) Granted for Keytruda Plus Chemotherapy as Neoadjuvant Treatment in Patients with High-Risk Early-Stage Triple-Negative Breast Cancer (TNBC)

Keytruda is an anti-PD-(L)1 cancer immunotherapy. This class of therapies helps detect and combat tumor cells by enhancing the capacity 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 leading the pack. Its global sales reached $14.38 billion in 2020, 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 specifically 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), leaving clinical treatment options very limited and primarily reliant on chemotherapy. Metastatic TNBC is one of the most aggressive and difficult-to-treat forms of breast cancer.

Regarding new drugs for TNBC, in March 2019, the United StatesFDAApproved 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 makes the Tecentriq plus Abraxane regimen 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 Sharp & Dohme’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. The 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 relevance (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 Keytruda treatment was 5.7 months. Based on 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 Outcome of Oncologic Drugs Advisory Committee (ODAC) for KEYTRUDA® (pembrolizumab) for Treatment of Patients With High-Risk Early-Stage Triple-Negative Breast Cancer (TNBC)