Sherene Loi, MD, PhD
The combination of pembrolizumab (Keytruda) and trastuzumab (Herceptin) reached an objective response rate (ORR) of 15.2% in patients with trastuzumab-resistant, PD-L1–positive, HER2-positive breast cancer, according to findings presented at 2017 San Antonio Breast Cancer Symposium (SABCS).
Results from the phase Ib/II PANACEA trial also showed that pembrolizumab/trastuzumab achieved a disease control rate of 24% in PD-L1–positive patients. Further, stromal tumor infiltrating lymphocytes (sTILs) were identified as a potential predictive marker. Among patients with sTIL levels ≥5%, ORR was 39% versus 5% in patients with sTIL levels <5%.
“The PANACEA study of pembrolizumab with trastuzumab in trastuzumab-resistant metastatic HER2-positive patients met its primary endpoint in the PD-L1–positive cohort,” lead study author Sherene Loi, MD, PhD, associate professor at Peter MacCallum Cancer Centre in Melbourne, Australia, working with the International Breast Cancer Study Group, said at a press conference at SABCS.
PANACEA (SG 45-13/BIG 4-13/KEYNOTE-014) accrued patients with centrally confirmed HER2-positive breast cancer, ECOG performance status of 0 or 1, and measurable disease per RECIST 1.1. There was no limit on the number of prior systemic therapies, and patients had to have progressed on trastuzumab (Herceptin) or T-DM1 (ado-trastuzumab emtansine; Kadcyla).
In the phase Ib part of the trial, PD-L1–positive patients received IV pembrolizumab at 2 mg/kg or 10 mg/kg plus trastuzumab every 3 weeks. In phase II, PD-L1–positive and –negative patients received 200 mg of IV pembrolizumab plus trastuzumab every 3 weeks.
Treatment was administered until progression, unacceptable toxicity, patient withdrawal, investigator decision, or a maximum of 2 years.
The primary endpoint of the phase II part of the study was ORR. Secondary outcome measures included progression-free survival (PFS), disease control rate, duration of response, duration of disease control, and overall survival (OS).
Overall, 146 patients were screened between February 2015 and April 2017 at 11 sites across 5 countries. Sixty-eight (53.5%) patients were PD-L1 positive. It was determined that 10.6% of patients were ineligible for the study because they were HER2 negative. Investigators enrolled 58 (39.7%) of the screened patients: 6 PD-L1+ patients in phase Ib, 40 PD-L1+ patients in phase II, and 12 PD-L1–negative patients in phase II.
At a median follow-up of 13.6 months, 3 (5%) patients remained on treatment and 46 (84%) patients had discontinued treatment. Some of the reasons for discontinuation included adverse events (AEs; n = 6), withdrawal of consent (n = 1), patient deterioration (n = 1), and death due to progressive disease (n = 1).
Across the cohorts, the median age was 50.5 years (range, 28-72), 56.9% of patients were ER-negative, and 43.1% of patients were ER-positive. All patients had received chemotherapy and a trastuzumab-containing regimen.
Loi noted that, “In the PD-L1+ cohort, the patients were numerically younger and there was a higher frequency of ER-negative disease.”
Over 80% of each cohort had previously received an additional anti-HER2 therapy. In the phase Ib, phase II PD-L1+, and phase II PD-L1–negative cohorts, 4, 29, and 9 patients, respectively, had prior T-DM1. Three, 10, and 4 patients, respectively, had prior pertuzumab (Perjeta).
The ORR was 17% in the phase I PD-L1+ group, comprising 1 complete response (CR). In the phase II PD-L1+ group, the ORR was 15%, comprising 1 CR and 5 partial responses (PRs). Seven patients in this cohort had stable disease (SD), 25 had progressive disease, and 2 were not evaluable.
There were no responses in the PD-L1–negative group. Two patients had SD, 9 had progressive disease, and 1 was not evaluable.
Among all PD-L1–positive patients, the median duration of disease control (CR, PR, or SD ≥6 months) was 11.1 months and the median duration of response was 3.5 months. At the time of the data cutoff, 5 patients continued without progression. Loi noted that 3 of these 5 patients have completed 2 years of pembrolizumab.
The median PFS among all PD-L1+ patients was 2.7 months (90% CI, 2.6-4.0) versus 2.5 months (90% CI, 1.4-2.7) in PD-L1–negative patients (P = .07). The 12-month PFS rates were 13% (90% CI, 6-22) versus 0, respectively.
Across all PD-L1+ patients, the median OS was 16.1 months (90% CI, 13.1 to not reached) versus 7.0 months (90% CI, 4.9-9.8) in the PD-L1–negative group (P = .0006). The 12-month OS rates were 65% (90% CI, 52-76) versus 12% (90% CI, 1-36), respectively.
Higher levels of sTILs were associated with improved response and disease control. Among all PD-L1+ patients, 41% had sTILs ≥5%. The disease control rate was 47% in patients with sTILs ≥5% versus 5% in patients with sTILs <5%.
“An [sTIL level] of 5% provides high sensitivity, high negative predictive value, and potentially high reproducibility amongst pathologists,” said Loi.
Safety was evaluated across all 58 patients. Most AEs were grade 1/2. The most common grade 1 AEs included fatigue (n = 7), diarrhea (n = 6), arthralgia (n = 6), headache (n = 4), nausea (n = 6), dyspnea (n = 2), and myalgia (n = 5). Grade 2 AEs included fatigue (n = 5), diarrhea (n = 2), arthralgia (n = 2), headache (n = 2), and dyspnea (n = 1). There was 1 case each of grade 3 and grade 4 dyspnea. No cardiac events were reported.
There were 11 all-grade immune-related AEs reported, including 6 that were grade ≥3. Four immune-related AEs resulted in discontinuation. Thyroid dysfunction across all grades occurred in 4 patients. There were 4 cases of pneumonitis across all grades, including 2 cases of grade ≥3 severity.
Activity for single-agent pembrolizumab was previously demonstrated in patients with heavily pretreated metastatic triple-negative breast cancer (TNBC). Data from cohort A of the phase II KEYNOTE-086 trial presented at the 2017 ASCO Annual Meeting showed an ORR of 4.7% (95% CI, 2.3-9.2), including a CR rate of 0.6% and a PR rate of 4.1%. The SD rate was 20.6%. The median duration of response was 6.3 months (range, 1.2+ to 10.3+).
Prior to those findings, data were reported at SABCS 2016 from the phase Ib KEYNOTE-012 trial, involving 32 patients with PD-L1–positive heavily pretreated TNBC who received single-agent pembrolizumab. The ORR was 18.5%, which included 1 CR (3.7%) and 4 partial PRs (14.8%). Additionally, seven patients had SD (25.9%), 1 of which persisted for ≥24 months.
Commenting on the next steps in the HER2-positive setting, Loi said, “Future directions for immunotherapy in metastatic HER2+ breast cancer should focus on combinations with effective anti-HER2 therapy, especially in low TIL patients.”
Loi S, Giobbie-Hurder A, Gombos A, et al. Phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive advanced breast cancer: results from the PANACEA study (IBCSG 45-13/BIG 4-13/KEYNOTE-014). Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS2-06.