Merck & Co. is detailing for the first time proof that immunotherapy can stop tumors from returning in patients with an aggressive type of early-stage breast cancer, a finding that the drugmaker plans to use to rebound from a regulatory rejection in March.
Results from a late-stage study of 1,174 patients showed a combination of Merck's Keytruda and chemotherapy, given before surgery to remove a tumor and followed by immunotherapy alone after, led to a 37% reduction in the risk of cancer's return or death compared to only chemotherapy in people with triple-negative breast cancer.
After a median follow-up of just over three years, nearly 16% of patients who received Keytruda and chemotherapy had signs of disease progression, such as recurrence, the formation of a new type of tumor or death. That compared to about 24% who had received chemo alone and experienced one of these "events." Drugmakers like Merck measure "event-free survival" as a way to gauge whether their treatments might benefit patients with early-stage cancers.
Researchers reported about 85% of people given Keytruda and chemo in the study were event-free after three years, versus just under 77% of those on only chemo.
Merck has shared the data with the Food and Drug Administration. If approved, Keytruda could become the first immunotherapy available for patients with early-stage breast cancer.
"This is, in my opinion, a milestone," said Peter Schmid, the study's lead investigator and the chair of cancer medicine at Barts Cancer Institute at Queen Mary University London. Schmid has consulted for Merck and other cancer drugmakers.
Immunotherapies like Keytruda, Bristol Myers Squibb's Opdivo and Roche's Tecentriq are approved for many types of cancers that have already spread. Merck's trial is part of a push by the companies to use immunotherapies earlier, when they might stop cancers from returning and becoming more deadly. A few approvals have already been granted for immunotherapies administered after surgery. Several additional trials are underway, as well as tests of drug regimens that start even earlier, before the removal of a tumor.
These studies have sparked debate about the benefits immunotherapy can offer patients when given earlier, in part because drugmakers are using interim measures to get treatments to market before proving they can extend lives.
Merck, for instance, first tried to win approval of Keytruda in early-stage triple-negative breast cancer based on an improvement in pathological complete responses, or the disappearance of cancers from tissue samples. An FDA advisory panel voted against Keytruda, however, and recommended the agency wait until event-free survival data showed a benefit. The regulator rejected Keytruda for the indication in March.
But by May, Merck said it had positive data on that measure and on Thursday revealed the specific results, which are important given the high recurrence rates for patients with triple-negative tumors. One 2019 study estimated 40% of triple-negative patients with Stage 1 to Stage 3 disease eventually have their tumors return. Cancers become progressively more deadly when they return or take root in different organs.
While delaying cancer recurrence is viewed as a proxy for a drug's ability to keep patients alive longer, that hasn't always been the case. Some cancer doctors are critical of the measure and as a result have been hesitant to use immunotherapies in early disease settings. A snap poll conducted during ASCO, the year's biggest meeting for cancer research, found a majority of oncologists would wait for survival data before prescribing an immunotherapy.
Merck's trial, known as Keynote-522, hasn't run for long enough for investigators to definitively determine whether the Keytruda-chemo regimen can extend patients' lives. Results are trending in that direction, however, as investigators reported a 28% reduction in the risk of death versus the chemo arm. The comparison is not yet considered statistically significant.
Schmid expects that eventually a survival benefit will be clear. There is a "strong link," he said, between recurrence and survival in triple-negative disease, as patients' cancers often return within three years and can kill them within another two.
Researchers found about 7% of Keytruda patients had more lethal "distant" cancers return, compared to 13% on chemotherapy, a sign of increased survival chances. Positive results were reported across different patient subgroups, including among those who still had cancer on biopsied tissue after surgery and those whose tumors didn't express a protein linked to immunotherapy response, he added.
Side effects were more commonly observed with Merck's drug, particularly the immune-mediated complications often associated with immunotherapy, which occured in about twice the number of patients on Keytruda than chemo alone.
Keytruda was also associated with an increased rate of hypothyroidism, a potentially irreversible change to thyroid function, though the condition can be managed with medication, Schmid said.
Cancer doctors may soon have to weigh those drawbacks against Keytruda's benefits, should the FDA approve the drug. They'll also have other issues to consider, such as who treatment would help the most or which phase of the before-and-after surgery regimen is more beneficial.
But the data show "we have a new standard of care, going forward," Schmid said. "I personally struggle to see how one wouldn't discuss this treatment option with a patient."