Ayala Pharmaceuticals Inc (ADXS)

[ubmmg]

Although we've been waiting for Advaxis to sign an IST for H&N cancer for a while, it looks like it may not happen at all. The competition (MRK) will have a PDUFA soon for Keynote-048 trial with good results, and we are no match. Just recall how pathetic H&N clinical data was for AXAL in combo therapy (durvalumab).

https://www.apnews.com/Business%20Wire/f9d11e4c0d404106b9aef952a44ac965

Merck’s KEYTRUDA® (pembrolizumab) Demonstrates Improved Overall Survival as First-Line Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma at Final Analysis of Pivotal Phase 3 KEYNOTE-048 Trial


Merck’s KEYTRUDA® (pembrolizumab) Demonstrates Improved Overall Survival as First-Line Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma at Final Analysis of Pivotal Phase 3 KEYNOTE-048 Trial
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KENILWORTH, N.J.--(BUSINESS WIRE)--May 31, 2019--

Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the presentation of the final analysis of the pivotal Phase 3 KEYNOTE-048 trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy and in combination with chemotherapy, for the first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #6000). Data include the first-time presentation of certain overall survival (OS) hypotheses from the KEYTRUDA in combination with chemotherapy study arm based on PD-L1 expression and the KEYTRUDA monotherapy study arm in the total patient population. Results of an interim analysis were presented at the European Society for Medical Oncology (ESMO) 2018 Congress and demonstrated superior OS outcomes for KEYTRUDA in combination with chemotherapy in the total population and KEYTRUDA monotherapy in patients whose tumors expressed PD-L1 with Combined Positive Score (CPS) ≥20 and CPS ≥1 compared with the EXTREME regimen, the current standard of care.

“It is exciting to see the full results from this trial, which is the first study to show superior overall survival over the current standard of care known as the EXTREME regimen,” said Dr. Danny Rischin, director of the department of medical oncology, Peter MacCallum Cancer Centre, Melbourne, Australia. “Patients with recurrent or metastatic head and neck cancer have a poor prognosis with limited treatment options. These findings underscore the potential of KEYTRUDA monotherapy and in combination with platinum-based chemotherapy to become important new treatment options.”

The new findings presented today from the final analysis showed that KEYTRUDA in combination with chemotherapy (carboplatin or cisplatin plus 5-FU) reduced the risk of death by 40% in patients whose tumors expressed PD-L1 with CPS≥20, demonstrating significantly longer OS (14.7 months [95% CI, 10.3-19.3]) compared with the EXTREME regimen (cetuximab with carboplatin or cisplatin plus 5-fluorouracil [5-FU]), the current standard of care (11.0 months [95% CI, 9.2-13.0]) (HR=0.60 [95% CI, 0.45-0.82]; p=0.0004). For the dual primary endpoint of progression-free survival (PFS), statistical significance was not achieved for KEYTRUDA in combination with chemotherapy in the CPS≥20 population compared with the EXTREME regimen (HR=0.73 [95% CI, 0.55-.97]; p=0.0162). New findings for the CPS ≥1 population showed KEYTRUDA in combination with chemotherapy reduced the risk of death by 35% in these patients, with significantly longer OS (13.6 months [95% CI, 10.7-15.5]) compared with the EXTREME regimen (10.4 months [95% CI, 9.1-11.7]) (HR=0.65 [95% CI, 0.53-0.80]; p<0.0001). Per the sequential testing strategy, superiority for PFS was not tested in this population (HR=0.82 [95% CI, 0.67-1.00]). Results for OS with KEYTRUDA monotherapy in the total population were consistent with the previously presented interim analysis, where non-inferiority was demonstrated (HR=0.83 [95% CI, 0.70-0.99]; p=0.0199), with a median OS of 11.5 months (95% CI, 10.3-13.4) for KEYTRUDA monotherapy in the total population compared with 10.7 months (95% CI, 9.3-11.7) for the EXTREME regimen. There was no difference in PFS between KEYTRUDA monotherapy in the total population and the EXTREME regimen (HR=1.34 [95% CI, 1.13-1.59]).


“As a company, Merck is committed to advancing research in this challenging treatment setting through our expansive head and neck cancer clinical research program,” said Dr. Jonathan Cheng, vice president, clinical research, Merck Research Laboratories. “The full data from KEYNOTE-048 illustrate the impact of KEYTRUDA as monotherapy and in combination with chemotherapy as potential new first-line treatment options for patients with recurrent or metastatic head and neck squamous cell carcinoma. We would like to sincerely thank the patients and investigators for their involvement in KEYNOTE-048.”

As previously announced, the U.S. Food and Drug Administration (FDA) has granted priority review for a new supplemental Biologics License Application (sBLA) seeking approval for KEYTRUDA as monotherapy or in combination with platinum and 5-FU chemotherapy for the first-line treatment of patients with recurrent or metastatic HNSCC based in part on data from the second interim analysis of KEYNOTE-048. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of June 10, 2019.

Study Design and Additional Data from KEYNOTE-048 (Abstract #6000)

KEYNOTE-048, a randomized, open-label Phase 3 trial (ClinicalTrials.gov, NCT02358031), evaluated KEYTRUDA in combination with chemotherapy or KEYTRUDA monotherapy, compared with the EXTREME regimen, as first-line treatment in patients with recurrent or metastatic HNSCC. The dual primary endpoints were OS and PFS. The secondary endpoints were PFS (at six months and 12 months), objective response rate (ORR) and time to deterioration in the Quality of Life Global Health Status/Quality of Life Scales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire and Safety. Duration of response (DOR) was evaluated as part of a pre-specified exploratory analysis. The primary and secondary endpoints, as well as exploratory DOR analysis, were evaluated in patients whose tumors expressed PD-L1 (CPS ≥20 and CPS ≥1) and in the total population, based on a fixed sequential testing strategy. Data cutoff for the final analysis was Feb. 25, 2019; data cutoff for the previously presented second interim analysis was June 13, 2018. Details of the OS benefit observed at the final analysis are below:


Summary of Overall Survival



Population (number of patients with event) Final Analysis Hazard Ratio (95% CI)
KEYTRUDA Monotherapy
PD-L1 CPS ≥20 (n=133) vs. EXTREME (n=122) 0.58 (0.44-0.78) b
PD-L1 CPS ≥1 (n=257) vs. EXTREME (n=255) 0.74 (0.61-0.90) b
Total Population (n=301) vs. EXTREME (n=300) 0.83 (0.70-0.99); p=0.0199 c
KEYTRUDA in Combination with
Chemotherapy

PD-L1 CPS ≥20 (n=126) vs. EXTREME (n=110) 0.60 (0.45–0.82); p=0.0004 a
PD-L1 CPS ≥1 (n=242) vs. EXTREME (n=235) 0.65 (0.53–0.80); p<0.0001 a
Total Population (n=281) vs. EXTREME (n=278) 0.72 (0.60-0.87) b
a Superiority demonstrated.
b No new statistical testing performed because population previously demonstrated superiority at interim analysis.
c Superiority not demonstrated.

The secondary endpoint of ORR was 42.9% for KEYTRUDA in combination with chemotherapy in patients whose tumors expressed PD-L1 with CPS ≥20 compared with 38.2% for the EXTREME regimen. The ORR was 36.4% in patients whose tumors expressed PD-L1 with CPS ≥1 for KEYTRUDA in combination with chemotherapy compared with 35.7% for the EXTREME regimen. The median DOR was 7.1 months (range, 2.1+ to 39.0+) for KEYTRUDA in combination with chemotherapy in patients whose tumors expressed PD-L1 with CPS ≥20 compared with 4.2 months (range, 1.2+ to 31.5+) for the EXTREME regimen. The median DOR was 6.7 months (range, 1.6+ to 39.0+) for KEYTRUDA in combination with chemotherapy in patients whose tumors expressed PD-L1 with CPS ≥1 compared with 4.3 months (range, 1.2+ to 31.5+) for the EXTREME regimen.

In the KEYTRUDA monotherapy arm, an analysis of the total patient population showed an ORR of 16.9% compared with 36.0% for the EXTREME regimen; the median DOR was 22.6 months (range, 1.5+ to 43.0+) compared with 4.5 months (range, 1.2+ to 38.7+) for the EXTREME regimen.

As previously reported, there were no new safety concerns identified with the use of KEYTRUDA in KEYNOTE-048. Grade 3-5 all-cause adverse events occurred in 54.7%, 85.1% and 83.3% of patients in the KEYTRUDA monotherapy, KEYTRUDA in combination with chemotherapy and EXTREME regimen arms, respectively. Adverse events resulting in discontinuation occurred in 12.0%, 32.6% and 27.5% of patients in the KEYTRUDA monotherapy, KEYTRUDA in combination with chemotherapy and EXTREME regimen arms, respectively. Treatment-related deaths occurred in 1.0%, 4.0% and 2.8% of patients in the KEYTRUDA monotherapy, KEYTRUDA in combination with chemotherapy and EXTREME regimen arms, respectively. Grade 3-5 immune-mediated or infusion reactions occurred in 7.0%, 5.4% and 10.5% of patients in the KEYTRUDA monotherapy, KEYTRUDA in combination with chemotherapy and EXTREME regimen arms, respectively.

Additional Information About KEYNOTE-048

KEYNOTE-048 enrolled 882 patients with recurrent or metastatic HNSCC who were randomized to one of three regimens as first-line therapy, as follows:

KEYTRUDA monotherapy (200 mg fixed dosed every three weeks [Q3W]) for up to 24 months (n=301); or
KEYTRUDA (200 mg fixed dose Q3W) in combination with cisplatin (100 mg/m 2 IV Q3W) or carboplatin (AUC 5 IV Q3W) plus 5-FU (1000 mg/m 2 /day IV continuous from Day 1-4 Q3W (maximum six cycles), followed by additional KEYTRUDA monotherapy maintenance therapy until progression of disease, toxicity or until the patient had received a maximum of 24 months total treatment (n=281); or
EXTREME regimen including cetuximab at a loading dose (400 mg/m 2 IV) followed by weekly doses (250 mg/m 2 IV) in combination with cisplatin (100 mg/m 2 IV Q3W) or carboplatin (AUC 5 IV Q3W) plus 5-FU (1000 mg/m 2 /day IV) continuous from Day 1-4 Q3W (maximum six cycles), followed by additional cetuximab monotherapy maintenance therapy until progression of disease or toxicity (n=300).
About Head and Neck Cancer

Head and neck cancer describes a number of different tumors that develop in or around the throat, larynx, nose, sinuses and mouth. Most head and neck cancers are squamous cell carcinomas that begin in the flat, squamous cells that make up the thin surface layer of the structures in the head and neck. Two substances that greatly increase the risk of developing head and neck cancer are tobacco and alcohol. It is estimated that there were more than 887,000 new cases of head and neck cancer diagnosed and over 453,000 deaths from the disease worldwide in 2018. In the U.S. alone, it is estimated that there will be more than 65,000 new cases of head and neck cancer diagnosed and over 14,000 deaths from the disease in 2019.