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On February 14, Merck announced the interim results of the Ib/II umbrella study KEYNOTE-365 at the American Society of Clinical Oncology Urology Tumor Symposium (ASCO GU).

KEYNOTE-365 is a developmental, multicenter, multi-cohort, non-randomized study evaluating the efficacy of a fixed dose of Keytruda (200 mg once every 3 weeks) in combination with multiple drug treatments for castration-resistant prostate cancer (mCRPC). Safety, plans to recruit 400 patients, divided into 4 queues, each of which was evaluated separately. The primary endpoint was safety, prostate specific antigen (PSA) response rate (respective of PSA reduction of more than 50%), and overall response rate (ORR); secondary endpoints included disease control rate, radiological progression-free survival (rPFS) ), the overall survival period. The results of three queues were announced at the ASCO GU conference.

A cohort: 41 patients who received too much statins and another chemotherapy drug and a second-generation anti-hormonal therapy. Keytruda (200 mg, q3w) + Lynparza (400 mg, bid) was administered.

The results showed that the PSA response rate of the A cohort was 12% (5/41), and the disease control rate (more than 6 months) was 29%. Among them, the PSA response rate of patients with evaluable lesions was 14% (4/28), the median PSA progression time was 15.3 weeks, the ORR was 7% (2/28, all partial responses), and the disease control rate was 32%; The PSA response rate for patients without evaluable lesions was 8% (1/13), the median PSA progression time was 18.1 weeks, and the disease control rate was 23%. In addition, the median rPFS of the A cohort was 4.7 months, the 6-month radiological progression-free survival rate was 48%, the median OS was 13.5 months, and the 6-month survival rate was 73%.

In terms of safety, the proportion of patients with grade 3 or 4 treatment-related adverse events was 49% in the A cohort, with the most common (≥10%) being anemia (27%). The incidence of immune-mediated related adverse events was 49%, mostly grade 1 or 2, the most common of which was hypothyroidism. One patient died of an unrelated treatment-related adverse event.

B cohort: 72 patients who had received previous treatment with abiraterone or enzalutamide but had not received chemotherapy were given Keytruda (200 mg, q3w) + docetaxel (75 mg) + prednisone (5 mg, bid ,oral).

The results showed that the PSA response rate of the B cohort was 31% (22/72), and the disease control rate (more than 6 months) was 57%. Among them, the PSA response rate of patients with evaluable lesions was 22% (8/36), the median PSA progression time was 24.1 weeks, the ORR was 14% (5/36, all partial responses), and the disease control rate was 50%; The PSA response rate was 39% (14/36) in patients without evaluable lesions, 30.4 weeks in median PSA, and 64% in disease control. In addition, the median rPFS of the B cohort was 8.3 months, and the 6-month radiological progression-free survival rate was 79%. The median OS data was not yet mature, and the 6-month survival rate was 96%.

In terms of safety, the proportion of patients with grade 3 to 5 treatment-related adverse events was 36% in the B-cohort, with the most common (≥10%) being neutropenic fever (12%). The incidence of immune-mediated adverse events was 33%, the most common of which were injection site reactions (11%) and colitis (10%). Two patients died of treatment-related pneumonia.

C cohort: 69 patients who had previously received abiraterone but had not received chemotherapy. Keytruda (200 mg, q3w) + enzalutamide (160 mg, qd, orally) was administered.

The results showed that the PSA response rate of the C cohort was 26% (18/69), and the disease control rate (more than 6 months) was 33%. Among them, the PSA response rate was 40% (10/25), the median PSA progression time was 18.4 weeks, and the ORR was 20% (CR 8%, 2/25; PR 12%, 3/25). The disease control rate was 32%; the PSA response rate was 18% (8/44) in the absence of evaluable lesions, the median PSA progression time was 12.4 weeks, and the disease control rate was 34%. In addition, the median rPFS of the C cohort was 6.1 months, the 6-month radiological progression-free survival rate was 59%, the median response duration was 8.3 months, and the response time of 75% of patients could last more than 6 months. The OS data is not yet mature and the 6-month survival rate is 91%.

In terms of safety, the proportion of patients with grade 3 or 4 treatment-related adverse events was 41%, and the most common (≥10%) was rash (10%). The incidence of immune-mediated adverse events was 41%, with the most common being severe skin reactions (20%) and hypothyroidism (13%). No patients died of treatment-related adverse events.

Based on the clinical data of the above three cohorts, Merck has announced the launch of three new clinical phase III clinical trials of prostate cancer, Keytruda+Lynparza (KEYLYNK-010, NCT03834519), Keytruda+Docetaxel+Poni Pine (KEYNOTE-921, NCT03834506), a combination of Keytruda + enzalutamide (KEYNOTE-641, NCT03834493).

Prostate cancer is a male androgen-dependent tumor that stimulates the growth and progression of prostate cancer cells. Traditional endocrine therapies include castration therapy to block testicular-derived androgens (surgical resection of bilateral orchiectomy, injection of goserelin, etc.) and anti-male therapy (oral anti-androgenic drugs) to block adrenal-derived androgens. However, as the disease progresses, although the testes and adrenal-derived androgens are blocked, the ability of the tumor cells to biosynthesize androgens is increased, and the mutated androgen receptor (AR) is more sensitive to low levels of androgens. It can still drive disease progression, and the disease state at this time is prostate cancer (CPRC) in the castration resistance phase.

Merck’s previous clinical trials for prostate cancer include the Phase II KEYNOTE-199 study (Keytruda Monotherapy), and the Phase III PROfound study (Lynparza Monotherapy Study) and PROPEL Study (Lynparza+ Abit) in collaboration with AstraZeneca Dragon first line treatment mCRPC).

The PD1 company targeting prostate cancer is not the only Merck. BMS also launched a Phase II study of Opdivo+Rubraca (PARP Inhibitor) in collaboration with Clovis Oncology in 2017, and BMS has a series of similar clinical trials of Opdivo in combination with chemotherapy or anti-male drugs for prostate cancer. processing.

At this ASCO GU conference, BMS published an interim analysis of the phase II CheckMate-650 study of PD-1+CTLA4 for patients with prostate cancer who had received first-line anti-male therapy but had not received chemotherapy, with an ORR of 25%. Johnson & Johnson also announced that its PARP inhibitor Zejula achieved a 40% response rate in a phase II study of patients with BRCA-mutant prostate cancer.

However, after launching the new three Phase III studies, Merck is currently the largest PD-1/PD-L1 clinical study in the prostate cancer field and the only company to use OS as a common endpoint in Phase III studies. Merck’s determination in the field of prostate cancer is evident, said Roy Baynes, chief medical officer, who has shown that Keytruda can be the potential for basic prostate cancer therapy.

Globally, prostate cancer is the second most common type of cancer in men. About one in nine men will be diagnosed with prostate cancer during their lifetime. In 2018, there are approximately 1.3 million newly diagnosed patients worldwide. In the United States in 2019, an estimated 174,650 patients will be diagnosed with prostate cancer. About 20% of patients will progress to castration to resist prostate cancer within 5 years after diagnosis, and castration-resistant prostate cancer patients usually metastasize within 2 years of diagnosis.

So far, the huge victory in the lung cancer market has helped Merck East Keytruda’s market share exceed that of BMS’s Opdivo, but the number of lung cancer cases in developed countries has decreased significantly, the number of smokers has decreased, and the number of patients with prostate cancer has increased with the elderly. And there is a clear upward trend, so the front cancer is likely to be the new main battlefield after Merck is regarded as lung cancer.

Just a few days ago, Merck also announced the recent submission of Keytruda + axitinib for the treatment of advanced renal cell carcinoma sBLA, which is a new growth point for Keytruda after lung cancer.

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