Pembrolizumab regimen extends EFS in early-stage triple-negative breast cancer
The use of pembrolizumab with neoadjuvant platinum-based chemotherapy and as monotherapy in the adjuvant setting extended EFS among patients with early-stage triple-negative breast cancer, according to results of the randomized phase 3 KEYNOTE-522 trial.
OS data remained immature but “a very strong signal” has emerged during relatively short follow-up, according to researcher Peter Schmid, MD, PhD, FRCP, clinical director of St. Bartholomew Breast Cancer Centre in London and lead of the Centre for Experimental Cancer Medicine at Barts Cancer Institute.
The findings — presented during an ESMO Virtual Plenary session — support this regimen as a new standard of care for this patient population, Schmid said.
“These results show a substantial and meaningful benefit with immune therapy,” Schmid told Healio. “We see a clear efficacy benefit and the adverse-event profile is consistent with what we know about immune therapy-chemotherapy combinations, with no new safety signals.”
Trial design
Triple-negative disease is the most aggressive breast cancer subtype. It accounts for 15% to 20% of breast cancer cases and disproportionately affects young women. The majority of cases are diagnosed at stage II (43%) or stage III (19%), according to study background.
Neoadjuvant chemotherapy is the current standard for early-stage disease, and patients who achieve pathologic complete response achieve longer EFS and OS. However, recurrence risk and mortality remain high, demonstrating the need for novel therapies that can improve the effectiveness of neoadjuvant chemotherapy.
In KEYNOTE-522 — the first phase 3 trial to evaluate immunotherapy for early breast cancer — researchers assessed the addition of the anti-PD-1 monoclonal antibody pembrolizumab (Keytruda, Merck) to neoadjuvant chemotherapy, followed by adjuvant pembrolizumab.
The trial included 1,174 adults with previously untreated, nonmetastatic, centrally confirmed triple-negative breast cancer. All patients had stage T1c N1-2 or T2-4 N0-2 disease.
Researchers assigned 784 patients to 200 mg pembrolizumab every 3 weeks in combination with neoadjuvant chemotherapy (four cycles of paclitaxel and carboplatin, followed by four cycles of doxorubicin or epirubicin plus cyclophosphamide). The other 390 patients chemotherapy plus placebo.
All patients underwent definitive surgery and received radiation therapy as indicated. Depending on randomization, they received adjuvant pembrolizumab or placebo. Adjuvant treatment continued for up to nine cycles, or until disease recurrence or unacceptable toxicity.
Pathologic complete response — defined as ypT0/Tis ypN0, meaning clearance of the cancer from the breast after chemotherapy — and EFS served as dual primary endpoints.
Secondary endpoints included OS, efficacy in the subset of patients with PD-L1-positive disease, and safety.
Treatment groups were well-balanced with regard to age, ECOG performance status, PD-L1-positivity, tumor size and nodal involvement.
EFS, OS results
Results of prior interim analyses showed the neoadjuvant pembrolizumab-chemotherapy regimen induced a significantly higher pathologic complete response rate and appeared associated with a favorable trend in EFS.
During the ESMO Virtual Plenary, Schmid presented results of a prespecified interim analysis performed after median follow-up of 39.1 months.
At that time, 123 patients (15.7%) assigned pembrolizumab and 93 patients (23.8%) assigned placebo had experienced EFS events (HR = 0.63; 95% CI, 0.48-0.82).
“The EFS data had been consistent throughout the two previous interim analyses, even though the results did not meet the predefined boundary for statistical significance,” Schmid said. “I was expecting the trial to demonstrate a significant and clinically meaningful benefit at some point, so I am not surprised to see that happen. To me, it was a question of when, not if.”
Median EFS had not been reached in either treatment group; however, researchers reported a higher 36-month EFS rate among patients assigned pembrolizumab (84.5% vs. 76.8%).
Researchers observed the PFS benefit with pembrolizumab across all key subgroups, with no significant differences based on PD-L1 or nodal status.
The most common EFS event was distant recurrence, experienced by 60 patients (7.7%) assigned pembrolizumab and 51 patients (13.1%) assigned placebo.
“Even with relatively short follow-up, already a substantial number of patients — 24% of those who received neoadjuvant chemotherapy alone — experienced disease recurrence,” Schmid said. “This is an aggressive disease and, for the first time, we can now prevent more than a third of those recurrences. This is a very significant result from the patient perspective.”
Researchers observed higher 36-month EFS rates with pembrolizumab among patients who achieved pathologic complete response after neoadjuvant chemotherapy (94.4% vs. 92.%), as well as those who had not achieved pathologic complete response (67.4% vs. 56.8%).
“We are seeing a substantial benefit with immune therapy among patients who had residual disease at the time of surgery,” Schmid said. “That tells me there is a chance we are modifying the biology of this disease, and that gives me a lot of hope.”
Results also showed a reduction in distant disease progression events with pembrolizumab vs. placebo (12.8% vs. 20.3%; HR = 0.61; 95% CI, 0.46-0.82), with 3-year distant RFS rates of 87% with pembrolizumab vs. 80.7% with chemotherapy alone.
Follow-up for OS is ongoing. By data cutoff, 10.2% of patients who received immune therapy plus chemotherapy and 14.1% of those assigned chemotherapy alone had died. The OS difference between groups had not reached statistical significance (HR = 0.72; 95% CI, 0.51-1.02).
“I believe that is still a substantial result even though, based on the statistical design, it is not yet statistically significant,” Schmid told Healio. “I look at it the same way I view the EFS results in that it is a matter of time.
“Patients with triple-negative breast cancer can have recurrences at 4 or 5 years,” Schmid added. “Patients who develop distant recurrence will pass away due to breast cancer so, unfortunately, we will see this gap between the two treatment groups widen.”
Safety profile
A comparable percentage of patients in the pembrolizumab and placebo groups experienced grade 3 or higher treatment-related adverse events (77.1% vs. 73.3%). A comparable percentage of patients each group experienced treatment-related adverse events that led to death (0.5% vs. 0.3%), though a higher percentage of patients assigned pembrolizumab experienced events that led to discontinuation of any drug (27.7% vs. 14.1%).
A considerably higher percentage of patients assigned pembrolizumab experienced immune-mediated adverse events (any grade, 43.6% vs. 21.9%; grade 3 to grade 5, 14.9% vs. 2.1%).
“Most immune-mediated adverse events occurred in the neoadjuvant phase, were low grade and [were] manageable with treatment interruption, steroid administration and/or hormone replacement,” Schmid said.
Next steps
In February, FDA’s Oncologic Drugs Advisory Committee (ODAC) unanimously recommended deferring a decision on accelerated approval of pembrolizumab for this patient population due in part to concerns at that time about immature EFS and OS data.
“Now we have long-term data that show we’re not just increasing response rates, but we’re preventing recurrences. That is a meaningful result,” Schmid told Healio. “It is not up to me to comment on what the FDA and ODAC will do but, as a clinician, I absolutely would like to see this treatment regimen available to patients.
“We clearly have increased efficacy with immune therapy in this setting,” he added. “There are side effects with this treatment, but we have a lot of experience managing them and possibly preventing them. When you balance the efficacy with the safety data, I would be very disappointed if this combination wasn’t considered.”
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