Merck & Co. on Monday announced detailed interim results from the Phase III Keynote-048 study evaluating Keytruda (pembrolizumab) monotherapy for the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The company reported in July that the trial met its primary endpoint of overall survival (OS) in patients whose tumours expressed PD-L1.
The drugmaker said that in patients whose tumours expressed PD-L1 with a combined positive score (CPS) of at least 20, Keytruda monotherapy improved OS by 39 percent compared to the EXTREME regimen, which consists of Merck KGaA's Erbitux (cetuximab) plus cisplatin or carboplatin, in combination with 5-fluorouracil (5-FU). Further, in patients whose tumours expressed PD-L1 with a CPS of at least 1, Keytruda improved OS by 22 percent. Merck added that Keytruda in combination with chemotherapy improved OS compared to the EXTREME regimen by 23 percent.
"Patients with PD-L1 expression live longer when they have initial treatment with [Keytruda]," commented lead investigator Barbara Burtness, adding "it is thrilling to see these new data, which have the potential to alter the standard of care in the first-line treatment of head and neck cancer."
The trial randomised 882 patients to receive Keytruda monotherapy, Keytruda plus cisplatin or carboplatin, in combination with 5-FU, or the EXTREME regimen. The study's dual primary endpoints were OS and progression-free-survival (PFS), which were evaluated in patients whose tumours expressed PD-L1 with a CPS of at least 20 and CPS of at least 1, as well as in the total population, regardless of PD-L1 expression.
At the European Society for Medical Oncology (ESMO) congress on Monday, Merck said that OS in patients with CPS of at least 20 was significantly longer with Keytruda monotherapy at 14.9 months compared to 10.7 months for the EXTREME regimen. The company added that there was no difference in PFS between the groups, while objective response rate (ORR), which was a secondary goal, was 23.3 percent for Keytruda and 36.1 percent for the EXTREME regimen. In addition, median duration of response (DOR), which was another secondary endpoint, was longer with Keytruda at 20.9 months, versus 4.2 months for the EXTREME regimen.
Merck noted that in the group of patients with CPS of at least 1, OS was significantly longer with Keytruda monotherapy at 12.3 months, versus 10.3 months for the EXTREME regimen, while there was no difference between the groups for PFS. Further results showed that ORR was 19.1 percent for Keytruda, compared to 34.9 percent for the EXTREME regimen, while the median DOR was 20.9 months and 4.5 months, respectively.
The drugmaker added that OS in the total population was significantly longer with the Keytruda and chemotherapy combination at 13 months compared to 10.7 months for the EXTREME regimen. Again there was no difference in PFS between the study arms, while ORR was 35.6 percent for the Keytruda combination and 36.3 percent for the EXTREME regimen.
Burtness noted that compared to standard care, Keytruda alone had a lower response rate and numerically shorter PFS, but significantly longer OS. Burtness said that Merck's drug "appears to prolong life even when the cancer continues to grow, suggesting that it should be a first-line therapy in recurrent and metastatic head and neck cancer." However, Burtness added "whether [Keytruda] is given alone or with chemotherapy may depend on PD-L1 expression and we are conducting analyses to answer this question."
Merck said that it plans to seek expanded FDA approval of Keytruda for a first-line HNSCC indication based on data from the Keynote-048 study, with the filing also including results from the Phase III Keynote-040 trial. The company explained that a submission to the FDA seeking clearance of the anti-PD-1 therapy as a second-line treatment for HNSCC based on Keynote-040 has been withdrawn.
Commenting on the findings for ESMO, Tanguy Seiwert of the University of Chicago Medicine, said the study "establishes PD-L1 CPS as a valid marker for head and neck cancer that should be routinely measured in these patients." However, Seiwert noted "the challenge is that treatment benefit is not equally distributed but depends on a biomarker. Hence, PD-L1 CPS expression will likely inform our choice between the two new options – [Keytruda] alone, with a favourable side-effect profile, and [Keytruda] combined with chemotherapy, which may be used in a larger group of patients."
Seiwert continued "higher PD-L1 expression is associated with more benefit, but the exact cut points have to be determined, and individual patient characteristics will play an important role as well." Seiwert suggested that "the usefulness of other biomarkers to select patients for treatment, such as tumour mutational burden, should also be examined."
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