© 2021 MJH Life Science and Cancer Network. all rights reserved.

© 2021 MJH Life Sciences™ and Cancer Network. all rights reserved.

Conference | San Antonio Breast Cancer Symposium

In a phase 3 trial, a pre-specified subgroup of patients with early triple-negative breast cancer who received neoadjuvant pembrolizumab combined with chemotherapy and subsequently received pembrolizumab monotherapy improved event-free survival.

The phase 3 KEYNOTE-522 study (NCT03036488) showed that compared with placebo, patients with early-stage triple-negative breast cancer (TNBC) have an event-free survival benefit when receiving neoadjuvant pembrolizumab (Keytruda) combined with chemotherapy. These results can be seen based on a report from the San Antonio Breast Cancer Symposium in 2021, across pre-designated subgroups.

The results of the main EFS analysis showed that the incidence of EFS events in 784 patients who received pembrolizumab combined with chemotherapy followed by pembrolizumab was 15.7%, compared with 390 in the placebo group who received placebo combined with chemotherapy. The incidence of EFS events in patients was 23.8% (HR 0.63; 95% CI, 0.48-0.82; P = .00031). The median follow-up time for the two cohorts was 39.1 months (range, 30.0-48.0). The 36-month EFS rates were 84.5% and 76.8%, respectively.

In addition to the main EFS analysis, the researchers also performed 5 additional EFS sensitivity analyses (SA). Each additional analysis includes 5 definitions of the same events as the main analysis: local disease progression, local recurrence, distant progressive disease, distant recurrence, and all-cause death that exclude definitive surgery. The main analysis and SA 1 also regarded the positive margin of the last operation and the second primary cancer as an EFS event; the two analyses have the same EFS event criteria, but have alternative review rules.

Other criteria added to each SA are as follows: SA 2 includes new anticancer therapies for metastatic disease as an EFS event, SA 3 includes a positive margin at the last surgery, and SA 4 only includes 5 EFS events shared by all analyses. SA 5 adds the positive margins of the last surgery, the second primary cancer (not breast cancer), and the second primary breast cancer.

In SA 1, 14.3% of patients experienced an event in the experimental group, compared to 21.5% in the control group (HR 0.64; 95% CI, 0.48-0.84). The 36-month EFS rates were 85.3% and 77.9%, respectively.

The incidence of EFS events in the SA 2 experimental group was 15.7%, compared with 23.8% in the control group (HR 0.63; 95% CI, 0.48-0.82). In SA 3, these rates were 15.6% and 23.1% (HR 0.65; 95% CI, 0.50-0.85), and the 36-month EFS rates were 84.6% and 77.5%, respectively. In SA 4, the incidence of EFS events in the experimental group and the control group were 14.8% and 22.6%, respectively (HR 0.63; 95% CI, 0.48-0.84). Finally, in SA, 16.1% of patients in the experimental cohort and 24.4% of patients in the control group had 5 events (HR 0.63; 95% CI, 0.48-0.82).

"The therapeutic benefit of pembrolizumab in each SA is consistent with the main analysis," said Peter Schmid, MD, Professor of Medicine at the Barts Centre for Cancer Research in London, UK. "This shows the robustness of the main EFS results. These results support pembrolizumab combined with platinum-containing neoadjuvant chemotherapy, followed by postoperative pembrolizumab as the new standard treatment for high-risk early TNBC patients."

Regardless of the lymph node status, pembrolizumab combined with chemotherapy followed by adjuvant pembrolizumab also improved EFS results. Among the lymph node-negative patients, the event reporting rate of the experimental group was 11.4%, while that of the control group was 18.6% (HR 0.58; 95% CI, 0.37-0.91). The 36-month EFS rate of the experimental group (n = 376) was 88.6%, while that of the control group (n = 194) was 82.2%. In the experimental group and the control group, the incidence of events in patients with lymph node-positive disease was 19.6% and 29.1%, respectively (HR 0.65; 95% CI, 0.46-0.91). The 36-month EFS rate of the experimental group (n = 408) was 80.7%, while that of the control group (n = 196) was 71.5%.

Regardless of the stage of the disease, patients have seen the benefits of adjuvant pembrolizumab plus chemotherapy. In the experimental group and the control group, the EFS event reporting rates of patients with stage II disease were 11.7% and 18.6%, respectively (HR 0.60; 95% CI, 0.42-0.86). The 36-month EFS rate of the experimental group (n = 590) was 88.6%, while that of the control group (n = 291) was 81.7%. For patients with stage III disease, the reported EFS events were 27.8% and 39.8%, respectively; the 36-month EFS rates were 71.8% (n = 194) and 62.0% (n = 98), respectively.

Regardless of the menopausal status, patients benefited, with HRs of 0.62 (95% CI, 0.42-0.91) and 0.64 (95% CI, 0.44-0.93), respectively, which are beneficial to the adjuvant treatment of pembrolizumab before and after menopause. patient. In addition, immunohistochemical results showed that patients with HER2 positive 2+ (HR, 0.73; 95% CI, 0.43-1.24) and patients with immunohistochemical HER2 status 0 to 1 (HR, 0.60; 95% CI, 0.44- 0.82) Benefits of the experimental program.

"All subgroups appear to have comparable EFS benefits, including those by lymph node staging and disease staging," Schmid added.

KEYNOTE-522 randomly divided a total of 1174 adult patients into experimental or placebo groups in a 2:1 manner. To qualify for the trial, patients must be newly diagnosed with T1c N1-2 or T2-4 N0-2 stage TNBC, ECOG performance status is not greater than 1, and be able to provide tissue samples for PD-L1 assessment. Stratification factors include lymph node status (positive and negative), tumor size (T1/T2 and T3/T4), and carboplatin regimen (once a week and once every 3 weeks).

The baseline characteristics between the two groups are well balanced. The positive rates of lymph nodes in the experimental group were 51.7% and 51.3% in the control group, and most of the patients in the two groups were in stage II disease (75.3% and 74.6%). In terms of menopausal status, 55.9% of patients in the experimental group were in pre-menopausal status, while 56.7% in the control group.

Both groups of the trial were treated in 2 neoadjuvant treatment stages, each of which consisted of 4 cycles and lasted for 12 weeks. Patients in the experimental group received chemotherapy plus 200 mg pembrolizumab every 3 weeks; people in the control group received a placebo instead of pembrolizumab. Both cohorts underwent surgery at 12 weeks. The experimental group continued to use pembrolizumab 200 mg during the 27-week adjuvant phase, and the other group continued to use placebo.

The primary endpoint of the trial is the pathology control rate (pCR) assessed by the local pathologist and the EFS assessed by the researcher. Secondary endpoints include alternative definitions of pCR, overall survival, and safety. Exploratory analysis includes EFS sensitivity analysis and EFS in patient subgroups.

Regarding safety, treatment-related adverse events (TRAE) in the experimental group and control group occurred in 98.9% and 99.7% of patients, respectively. 77.1% of patients in the experimental group had grade 3 to 5 AEs, compared with 73.3% in the control group. Severe AEs occurred in 34.1% of patients in the experimental group, 0.5% of AEs in this group resulted in death, and 27.7% resulted in drug withdrawal. AEs that led to death occurred in 0.3% of patients in the control group, and the incidence of drug discontinuation was 14.1%.

Common grade 1 to 2 TRAEs that occurred during the adjuvant treatment phase of the experimental group included arthralgia (8.5%), rash (6.0%), and itching (5.1%). The level 1~2 TRAEs of the control group included arthralgia (6.9%), fatigue (5.1%), fatigue (4.8%), etc. In the experimental group and the control group, the rate of any level of immune-mediated AE occurring in the adjuvant phase was 10.2% and 6.0%, respectively.

"The incidence of adverse events (AE) with pembrolizumab is very low, especially in adjuvant therapy," Schmid said.

Schmid P, Cortes J, Dent R, etc. KEYNOTE-522 Neoadjuvant pembrolizumab + chemotherapy vs placebo + chemotherapy followed by adjuvant pembrolizumab vs placebo for early TNBC studies: event-free survival sensitivity and subgroup analysis. Published in: San Antonio Breast Cancer Symposium 2021; December 7-10, 2021; virtual. Abstract GS1-01.