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Merck Updates Results From Early-Stage TNBC Keytruda Study On Path to Second FDA Approval Bid


NEW YORK – High-risk triple-negative breast cancer patients with early-stage tumors who received Merck's checkpoint inhibitor pembrolizumab (Keytruda) with chemo before surgery and then pembrolizumab again after surgery experienced significant event-free survival benefits in the Keynote-522 trial.

The pivotal Phase III trial randomized 1,174 patients to receive either the pembrolizumab-based regimen, or neoadjuvant chemotherapy and placebo followed by surgery and adjuvant placebo. Results from the trial's fourth planned interim analysis, which researchers presented Thursday during a virtual plenary session hosted by the European Society for Medical Oncology, showed that after a median follow-up of 39 months, patients who received the immunotherapy combination regimen saw a 37 percent reduction in the risk of events, including disease progression, recurrence, second primary cancer, or death from any cause, compared to patients receiving chemotherapy and placebo.

After three years, the event-free survival rate among patients who received the pembrolizumab regimen was 84.5 percent, versus 76.8 percent among patients in the comparator arm. While overall survival data are not yet mature, the interim analysis showed a trend toward improved overall survival with the chemotherapy regimen; among the pembrolizumab-treated patients, there was a 28 percent reduction in the risk of death versus the patients who received chemo and placebo.

"These data clearly support that pembrolizumab plus platinum-containing neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery should be a new standard of care treatment regimen for patients with high-risk, early-stage triple-negative breast cancer," Peter Schmid of Cancer Research UK Barts Center, Keynote-522's lead investigator, said in his presentation of the results.

Merck, optimistic about the clear event-free survival benefit, has already submitted the new data to the US Food and Drug Administration for review in the hopes of securing regulatory approval for the regimen. "In the case of an adjuvant study, disease-free or recurrence-free survival usually serves as the basis of a full approval in the US as a demonstration of clinical benefit," said Vicki Goodman, Merck's global VP and head of late-stage oncology development, expressing confidence that that agency will view the event-free survival advantage seen among pembrolizumab-treated patients as confirmation of clinical benefit and approve the indication.

"Obviously, we have to wait for feedback from the agency, but with other adjuvant studies, we have seen that similar endpoints have served as the basis for full approval," Goodman added.

Looking back

The new event-free survival data and Goodman's optimism follow Merck's earlier, unsuccessful attempt to secure FDA approval for the pembrolizumab regimen in this TNBC indication. In late 2020, Merck submitted results from Keynote-522's third interim analysis as part of a supplemental biological license application, which showed that pembrolizumab led to an improvement in the study's other primary endpoint, pathological complete response, but the data were not mature enough to show a clear event-free survival benefit.

At the time, there was a 7.5 percent difference in pathological complete response rates between the two arms, with 63 percent of pembrolizumab-treated patients experiencing a pathological complete response compared to 55.6 percent of patients on chemo and placebo. The drugmaker argued in favor of approval based on these data pointing to a handful of studies suggesting that pathologic complete response was reasonably likely to predict survival benefit. Plus, the survival data at the time, while not mature, reflected a trend toward benefit with the checkpoint inhibitor.

Regulators, however, did not agree. Rather than granting approval based on pathological complete response data, the agency decided to delay its decision, issuing a complete response letter to Merck in March requesting additional data. The agency, which was also keen to see survival data, had followed the unanimous advice of its Oncologic Drugs Advisory Committee to delay approval.

During the ODAC meeting in February, committee members had heated exchanges with Merck representatives and enthusiastic Keynote-522 investigators. In casting their votes, most ODAC members commented it would be premature to approve the regimen ahead of survival data, since the associated toxicities — both financial and physical — were higher with the immunotherapy.

"We owe it to the women who agreed to be part of this trial to make sure that the integrity of this science is maintained so that we have a good answer when we're done, and I'm not sure we do," said ODAC member Daniel Hayes of University of Michigan during the February meeting. "I was not impressed that we're there yet."

Questions answered, others remain

Some of those ODAC members who were largely concerned that the pathological complete response benefit seen in the study would not translate into a survival benefit may be less worried now having seen the event-free survival data. Even so, several questions that the members raised during that February meeting remain unanswered, including how much of the event-free survival benefit seen in the trial can be attributed to continued treatment with pembrolizumab in the adjuvant.

Keynote-522 was designed to evaluate event-free survival following four cycles of pembrolizumab plus paclitaxel and carboplatin and four cycles of pembrolizumab and cyclophosphamide plus either doxorubicin or epirubicin, then surgical tumor resection, then nine additional cycles of pembrolizumab after surgery. As such, the event-free survival calculation incorporates both the pre- and post-surgery immunotherapy treatment and there is no way to be sure that the neoadjuvant immunotherapy did not single-handedly account for the benefit.

"One uncertainty built into this trial design is that all patients randomized to the experimental arm are planned to receive neoadjuvant and adjuvant pembrolizumab," Mirat Shah, a medical oncologist and FDA clinical reviewer, noted during the February ODAC meeting. "Therefore, it is not possible to determine the relative contribution of the neoadjuvant and adjuvant portions of treatment on an observed event-free survival or overall survival result."

Even with the event-free survival and pathologic complete response benefit, some still feel that more data is needed to clarify the contribution of the continued adjuvant treatment for patients who both did and did not achieve a pathological complete response after the neoadjuvant treatment. In a discussion of the updated Keynote-522 data following the ESMO virtual plenary presentation, Giuseppe Curigliano of University of Milan pointed out this uncertainty, and that ongoing trials — including Merck's S1418 trial evaluating adjuvant pembrolizumab in TNBC patients with minimal residual disease following surgery — may help shed light on this question.

"As a research community, we need to look much more carefully into what is the optimal duration [of adjuvant pembrolizumab]," Lisa Carey of University of North Carolina Chapel Hill added with respect to this question.

Merck's Goodman, however, viewed any lingering concerns about the relative benefit of adjuvant pembrolizumab as a framing problem. In her description of the study design, in Keynote-522, patients didn't receive pembrolizumab and chemo in the neoadjuvant setting and then pembrolizumab again in the adjuvant setting, but rather received one long continuous immunotherapy regimen with surgery in between.

"What we're evaluating here is whether the addition of pembrolizumab both preoperatively in combination with standard-of-care chemotherapy and then post-operatively on its own improves outcomes … We view this as one pembrolizumab regimen," she said. "Oftentimes with adjuvant treatments, you give a drug for approximately a year, and that's how we're viewing this. It's just that it's broken into a preoperative phase and a postoperative phase."

To be sure, both Curigliano and Carey agreed that the available data from Keynote-522 demonstrates the benefit of the entire course of therapy and that, unless additional data end up supporting a more nuanced approach, the adjuvant pembrolizumab should be included in treatment for all eligible patients.

"You have to deal with the data as we have them right now," Carey said, noting that because the vast majority of serious adverse events on the trial were observed during the neoadjuvant phase, the risks of continuing on with adjuvant pembrolizumab are perhaps less related to physical toxicities than to concerns of high costs, accessibility, and convenience.

Role of new therapies  

Another lingering uncertainty among experts is how the pembrolizumab regimen will stand up in the fast-evolving TNBC treatment landscape since Keynote-522 began back in 2017. For instance, the PARP inhibitor olaparib (Merck/AstraZeneca's Lynparza) has since shown a benefit as adjuvant treatment for patients with BRCA1/2-mutated TNBC. The Keynote-522 trial, however, did not test patients for germline mutations in these genes.

"The good news is that we can combine PARP inhibitors with checkpoint inhibitors," Curigliano said, emphasizing that additional studies will be needed to determine which patients should receive which treatments, or perhaps combinations of treatments. "Pragmatism will be required to maximize the benefit achieved with our new treatments."

The chemotherapy drug capecitabine, moreover, has entered the landscape as a potential option for TNBC patients whose cancers are resistant to paclitaxel or anthracycline-containing chemo drugs. This further complicates the Keynote-522 trial, since data supporting capecitabine in the adjuvant setting were not yet available when the trial began, leading investigators to compare adjuvant pembrolizumab to a placebo, which Goodman called the "standard follow-up watch-and-wait approach."

"There is an apparent small benefit to giving capecitabine in that post-operative setting, but we designed the trial on the basis of the best standard of care at the time," Goodman said.

Finally, the question of predictive biomarkers to guide treatment remains somewhat of a gray area in light of Keynote-522. The trial found no difference in outcomes according to PD-L1 expression status and did not screen patients for BRCA1/2 mutations or other predictive biomarkers. High-risk patients were defined by clinical markers such as nodal status and tumor size.

"If we could get clear predictors, that would be incredibly helpful," Schmid said. "Some patients do well with very little treatment, and some need a whole lot." Going forward, Schmid agreed that an investigation into biomarkers of response to these regimens would be valuable for homing in on which patients might be eligible for chemotherapy or immunotherapy de-escalation.

That said, biomarker analyses — be they analyses of immune signatures, changes in tumor microenvironment, or otherwise — will need to consider the possible differences between tumor tissue resected at the time of surgery and residual tumors. "There's a multitude of different research questions that will result out of this and other trials … that will help us to fine-tune the treatment," Schmid said.

Even though the trial was decidedly positive and could lead to a new treatment option for patients with this particularly aggressive breast cancer subtype, narrowing the pool of patients for whom this full regimen is beneficial would be particularly valuable in light of the financial toxicities associated with the whole course. As Curigliano pointed out, in the US, the price of a standard, full course of chemo is somewhere between $30,000 and $40,000, whereas the estimated cost of adding pembrolizumab to chemotherapy is $180,000.

"I don't believe all the countries in the world can afford these prices," he said, adding that an extensive effort will be required to improve the access to immunotherapy in this setting, particularly in low- and middle-income countries.  

With this in mind, Schmid underscored that the fact that the trial was positive — and may, indeed, lead to regulatory approval in this patient population — does not mean that researchers should throw in the towel just yet.

Schmid noted that researchers have a "rich source of tissue and other biological materials," that they can use to identify best responders and non-responders. "This is a milestone," he said. "We have a positive trial. Now, it leaves a lot of work, because there are still a lot of questions to answer."