Merck & Co. has failed in an attempt to repeat Keytruda’s metastatic head and neck cancer success in locally advanced disease. But experts still see reasons to keep their hopes up for the drug in early stages of this tumor type.
Adding Keytruda to standard chemoradiation therapy showed a positive trend toward delaying disease worsening in locally advanced head and neck squamous cell carcinoma. But the combination only pared down the risk of disease progression or death by 17% over chemoradiation alone, failing to cross the statistical significance threshold.
In patients whose tumors expressed PD-L1, the Keytruda combo performed better, with a 20% reduction in the risk of progression or death over chemoradiation alone. Those with PD-L1-negative tumors experienced no obvious difference between the two treatment arms. The results, from the Keynote-412 trial, are presented at the ongoing European Society for Medical Oncology congress 2022.
Because of the failure, SVB Securities analyst Daina Graybosch, Ph.D., has removed $1.5 billion from Keytruda’s peak sales estimate. But not all is lost.
While the trial failed to hit its goal, it still suggests the addition of Keytruda had a “clinically meaningful effect” on slowing disease progression, study lead Jean-Pascal Machiels, M.D. Ph.D., at the Belgium’s Cliniques Universitaires Saint-Luc, said in a statement facilitated by ESMO.
“In addition, our data support the hypothesis that PD-L1 expression measured by [combined positive score] may be an informative predictive biomarker to better tailor the population that could benefit from [Keytruda] in this setting,” Machiels added.
Keytruda’s Keynote-412 flop follows a similar pattern as Pfizer and Merck KGaA’s PD-L inhibitor Bavencio which failed in the Javelin Head and Neck 100 trial, as patients with higher PD-L1 expression showed a benefit.
As Graybosch sees it, the problem may lie in the timing of Keytruda dosing.
In both trials, patients in the experimental arms first got a priming dose of Keytruda or Bavencio, followed by the PD-1/L1 inhibitor together with chemoradiation, and then PD-1/L1 maintenance. But a recent 80-subject phase 2 trial suggested that giving Keytruda entirely after chemoradiation rather than concurrently may be more effective, Graybosch noted.
In that small phase 2 study, Keytruda after chemoradiation had both a higher survival rate and also reduced disease progression or death over three years compared to using them in a similar combination pattern as in the current Keynote-412 trial.
Graybosch said she remained enthusiastic about the outcome from another phase 3 trial, coded Keynote-689, which is testing Keytruda both before and after surgery in patients with high-risk, resectable, locally advanced head and neck squamous cell carcinoma. She has given that indication a risk-adjusted peak sales estimate of $1.1 billion for Keytruda by 2027, according to a Monday note.
Thanks to a duo FDA approval in 2019, Keytruda monotherapy is allowed for PD-L1-positive, previously untreated metastatic head and neck cancer or in combination with chemo regardless of PD-L1 status. At that time the chemo regimen approved for use alongside Keytruda was platinum chemo plus a combo known as 5-FU. But 5-FU is associated with several toxicities, inconvenience to patients and other complications.
At ESMO congress 2022, Keytruda also released data from the ongoing phase 4 Keynote-B10 trial, which found that using another commonly used and more tolerable chemotherapy, paclitaxel, instead of 5-FU also worked alongside Keytruda in front-line head and neck cancer. The new combo shrunk tumors in 43% of patients, and all patients lived a median 12.1 months, which was comparable to the median 13 months in the 5-FU regimen’s historical performance in the Keynote-048 trial.
Investigators of Keynote-B10 suggested in an abstract that the results could expand treatment options for front-line metastatic head and neck cancer patients.
Editor's Note: The story has been updated with additional peak sales estimates from Daina Graybosch.