Neoadjuvant Pembrolizumab Regimen Active in TNBC

Peter Schmid, MD, PhD

The combination of the PD-1 inhibitor pembrolizumab (Keytruda) and platinum/taxane chemotherapy in the neoadjuvant setting induced high rates of pathologic complete response (pCR) in patients with locally advanced triple-negative breast cancer (TNBC), according to preliminary findings from the phase Ib KEYNOTE-173 trial.¹

“The combination of immune checkpoint inhibitors and neoadjuvant chemotherapy is feasible and safe,” said lead study author Peter Schmid, MD, PhD, FRCP, and lead of the Centre for Experimental Cancer Medicine at Barts Cancer Institute, in an interview with OncLive. “We found a very promising, though preliminary, pCR rate in this trial.”

For the trial, Schmid and researchers set out to establish the safety, tolerability, and recommended phase II dose of neoadjuvant therapy as well as to understand which chemotherapy backbone induced the highest rates of response when paired with pembrolizumab.

Safety and tolerability served as the primary endpoints of the trial, with secondary endpoints of pCR, objective response rate (ORR), and overall survival (OS).

Women ≥18 years of age, with a new diagnosis of locally advanced TNBC, adequate organ function, and an ECOG performance status of 0 or 1 were eligible to enroll. A total of 60 patients were randomized to 1 of 6 cohorts with varying doses of a taxane-based chemotherapy alone or in combination with platinum chemotherapy for 4 3-week cycles, followed by 60 mg/m² of doxorubicin and 600 mg/m² of cyclophosphamide for another four 3-week cycles:

• 125 mg/m² of nab-paclitaxel (Abraxane) on days 1, 8, and 15 (cohort A; n = 10);
• 100 mg/m² of nab-paclitaxel on days 1, 8, and 15/carboplatin starting dose area under the curve (AUC) 6 day 1 (cohort B; n = 10);
• 125 mg/m² of nab-paclitaxel on days 1, 8, and 15/carboplatin starting dose AUC 5 day 1 (cohort C; n = 10);

• 125 mg/m² of nab-paclitaxel on days 1, 8, and 15/ carboplatin starting dose AUC 2 days 1, 8, and 15 (cohort D; n = 10);
• 80 mg/m² of paclitaxel on days 1, 8, and 15/carboplatin starting dose AUC 5 day 1 (cohort E; n = 10);
• 80 mg/m² of paclitaxel on days 1, 8, and 15/carboplatin starting dose AUC 2 days 1, 8, and 15 (cohort F; n = 10).

In all cohorts, pembrolizumab was given at a single dose of 200 mg on day 1 of cycle 1 and on the first day of each 3-week cycle thereafter. All patients underwent definitive surgery within 3 to 6 weeks of receiving 9 cycles of neoadjuvant therapy.

The median age of patients enrolled in the trial was 48.5 years (range, 26-71). The majority of patients had a primary tumor ≥T2 (92%) and nodal involvement (67%).

At the time of data cut-off in May 2018, results showed that 78.3% of patients (n = 47) completed neoadjuvant therapy. Of the 13 patients who discontinued neoadjuvant treatment, 9 stopped treatment due to adverse events (AEs), 2 to withdrawal, 1 to physician’s choice, and 1 to progressive disease. Fifty-eight patients had surgery, after which 90% (n = 54) remained on the study. Median follow-up across cohorts was 19.6 months (range, 4.0-27.4).

At the time of surgery, 60% of patients had achieved a pCR, defined as ypT0/Tis ypN0 (no invasive residual disease in breast or nodes) versus 57% of those who achieved a pCR defined as ypT0 ypN0 (no invasive or noninvasive residual disease in breast or nodes). The highest rates of pCR were achieved by patients who received nab-paclitaxel and carboplatin in cohorts B, C, and D.

ORR was higher in the cohorts of patients who received carboplatin (B-F; 90% [90% CI, 80%-96%]), than what was observed in cohort A (80% [90% CI, 49%-96%]). Two cases of disease progression were identified prior to surgery, both of which were from cohort A.

Patients who achieved a pCR were more likely to have higher 12- and 24-month event-free survival (EFS) rates than those who did not. In responders, the 12- and 24-months EFS rates were 100% and 88% compared with 97% and 66%, respectively, in non-responders. Similarly, patients who received platinum-based therapy had a higher likelihood of achieving a 12-month EFS.

“We’ve only seen 3 recurrences in the patients who had received platinum-free treatment,” said Schmid. “In the 50 patients who received platinum-based therapy, there has not been tumor recurrence.”

Notably, an exploratory analysis from the trial indicated a positive association between a patient’s levels of stromal tumor-infiltrating lymphocytes at baseline and subsequent achievement of pCR and ORR.²

AEs were assessed over the course of the study and for up to 30 days after surgery. Dose-limiting toxicities (DLT) were considered toxic if ≥3 of the first 6 patients or ≥4 of 10 patients reported a DLT.

Across all cohorts, 22 (36.7%) patients had DLTs, including 2 in cohort A, 4 each in cohorts B and F, and 6 each in cohorts C and D. The most common DLTs were febrile neutropenia (n = 9; 1 in cohort A, 2 each in cohorts B and C, and 4 in cohort D) and neutropenia (n = 7; 3 in cohort C, 1 each in cohorts A, B, D, and F). Based on these findings, cohorts A and E met the criteria for further exploration and establishment of a recommended phase II dose.

Among all patients who reported a treatment-related AE (TRAE), 90% were ≥grade 3. The most commonly noted TRAEs were neutropenia (n = 44; 73%), febrile neutropenia (n = 13; 22%), anemia (n = 12; 20%), and thrombocytopenia (n = 5; 8%). Eleven patients discontinued pembrolizumab due to TRAEs. Eighteen patients (30%) had an immune-related AE, the most common of which were hypothyroidism (n = 5; 8%) and hyperthyroidism (n = 3; 5%).

These findings serve as the basis for the ongoing KEYNOTE-522 trial investigating neoadjuvant pembrolizumab and chemotherapy followed by adjuvant pembrolizumab and chemotherapy in patients with high-risk, early-stage TNBC (NCT03036488).

References

1. Schmid P, Park YH, Muñoz-Couselo E, et al. KEYNOTE-173: phase 1b multicohort study of pembrolizumab (Pembro) in combination with chemotherapy as neoadjuvant treatment for triple-negative breast cancer. Presented at: the 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract PD5-01. https://bit.ly/2AQ1aI0.
2. Loi S, Schmid P, Cortés J, et al. Relationship between tumor-infiltrating lymphocytes and response to pembrolizumab + chemotherapy as neoadjuvant treatment for triple-negative breast cancer: phase 1b KEYNOTE-173 trial. Presented at: the 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract PS-10-09. https://bit.ly/2qstXMW.