Frontline Pembrolizumab Plus Chemo Shows Compelling PFS Improvement in PD-L1+ TNBC

Javier Cortes, MD

According to results from the phase 3 KEYNOTE-355 trial (NCT02819518), frontline pembrolizumab in combination with multiple chemotherapy agents, promotes statistically significant and clinically meaningful improvement in progression-free survival (PFS) in patients with metastatic triple-negative breast cancer (TNBC) who have high PD-L1 expression in their tumors, compared with the PFS observed with chemotherapy alone. The results were presented during the 2020 ASCO Virtual Scientific Program.¹

At a median follow-up of 26.1 months, results showed that the combination led to a median PFS of 9.7 months compared with 5.6 months for chemotherapy alone in this patient subgroup, translating to a 35% reduction in the risk of disease progression or death (HR, 0.65; 95% CI, 0.49-0.86; one-sided P =.0012).

In patients whose tumors had a PD-L1 CPS of 1 or higher, the median PFS was 7.6 months and 5.6 months for pembrolizumab/chemotherapy versus chemotherapy alone (HR, 0.74; 0.61-0.90; P = .0014), which was not determined to be statistically significant.

Moreover, in the intent-to-treat (ITT) population, the median PFS with pembrolizumab combined with chemotherapy was 7.5 months compared with 5.6 months with chemotherapy alone, leading to an 18% reduction in the risk of death (HR, 0.82; 95% CI, 0.69-0.97). Statistical significance was not tested in this patient population.

"Pembrolizumab and chemotherapy demonstrated a statistically significant and clinically meaningful improvement in PFS as compared with chemotherapy alone for the first-line treatment of metastatic TNBC with a PD-L1 CPS of 10 or higher tumors," lead study author Javier Cortes, MD, head of breast cancer and gynecological cancers at Hospital Universitario Ramon y Cajal in Madrid, Spain, and clinical investigator in the Breast Cancer Research Program at Vall d'Hebron Institute of Oncology in Barcelona, Spain, said in a presentation during the meeting.

"The inclusion of taxanes and a known taxane platinum-based regimen permits assessment of the clinical benefit of pembrolizumab in combination with several [used] chemotherapy partners. A trend toward improved efficacy with PD-L1 enrichment was observed in patients treated with pembrolizumab and chemotherapy," Cortes added. "These findings suggest a role for the addition of pembrolizumab to standard chemotherapy for the first-line treatment of [patients with] metastatic TNBC."

The results are from an interim analysis conducted by an Independent Data Monitoring Committee (IDMC), which showed that the addition of pembrolizumab to nab-paclitaxel (Abraxane), paclitaxel, or carboplatin/gemcitabine showed a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy alone in this patient population. In February 2020, the IDMC recommended that the study continue without changes, in order to evaluate overall survival (OS), which is the other primary end point of the trial.²

Pembrolizumab has been evaluated in metastatic TNBC and has demonstrated durable antitumor activity and manageable safety in the KEYNOTE-012³, KEYNOTE-086A⁴, KEYNOTE-086B⁵, and KEYNOTE-119⁶ studies. In these trials, treatment with single-agent pembrolizumab led to objective response rates (ORRs) of 18.5%, 5.3%, 21.4%, and 9.6%, respectively. Improved clinical responses were observed in patients with higher PD-L1 expression, and responses were more durable with pembrolizumab monotherapy than those elicited with chemotherapy.

Moreover, in the neoadjuvant setting, pembrolizumab plus chemotherapy demonstrated a pathologic complete response (pCR) rate of 60% in the KEYNOTE-173 trial.⁷ Based on these data, the FDA granted a breakthrough therapy designation in October 2019 to pembrolizumab and chemotherapy as a neoadjuvant treatment for patients with high-risk, early-stage TNBC. The phase 3 KEYNOTE-522 trial also showed that patients with newly diagnosed, operable, stage II/III TNBC, regardless of PD-L1 expression, benefited from pembrolizumab with a pCR rate of 64.8% versus 51.2% with placebo, representing an absolute difference of 13.6 percentage points (95% CI, 5.4%-21.8%; P = .00055).⁸

In the two-part, randomized, phase 3 KEYNOTE-355 trial, investigators evaluated pembrolizumab in combination with investigator's choice of either nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin compared with placebo plus 1 of the 3 chemotherapy agents in patients with previously untreated locally recurrent inoperable or metastatic TNBC.

Patients must have been at least 18 years old, had central determination of TNBC and PD-L1 expression, completed treatment with curative intent at least 6 months prior to first disease recurrence, had an ECOG performance status of 0 or 1, a life expectancy of 12 weeks or longer from randomization, adequate organ function, no use of systemic steroids, no central nervous system metastases, and had no active immune disease.

In part 1 of the open-label study, investigators evaluated the safety and tolerability of pembrolizumab in combination with 1 of the chemotherapy regimens in 30 patients.

In part 2, 847 patients were randomized 2:1 to receive either placebo (n = 281) or pembrolizumab (n = 566) at 200 mg intravenously (IV) on day 1 of each 21-day cycle plus either nab-paclitaxel at 100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle; paclitaxel at 90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle; or 1000 mg/m2 of gemcitabine and area under the curve (AUC) 2 of carboplatin on days 1 and 8 of each 21-day cycle. The trial was not designed to compare the efficacy of the different chemotherapy regimens, Cortes explained. Treatment was continued until disease progression or cessation of study therapy.

Patients were stratified by chemotherapy given on study, PD-L1 tumor expression (CPS of 1 or higher vs CPS of less than 1), and prior treatment with the same class of neoadjuvant/adjuvant chemotherapy (yes vs no).

The coprimary end points of the trial were PFS and OS in patients with PD-L1–positive tumors and in the ITT population. Secondary end points were ORR, duration of response, disease control rate, and safety.

Overall alpha was controlled at one-sided 0.025 and was split among PFS (0.005), OS (0.018), and ORR (0.002). The prespecified plan allowed the alpha from successful hypotheses to be passed to other hypotheses, Cortes said. PFS was assessed using a hierarchical strategy, and the final PFS assessment was performed at a second interim analysis, with a data cutoff date of December 11, 2019.

Baseline characteristics were well balanced between the 2 arms. The median age was 53 years, and approximately 39.7% of patients had an ECOG performance status of 1. Most patients had a PD-L1–positive CPS of 1 or greater (75.1%), and 37.8% of patients had a CPS of 10 or greater. Approximately 45% of patients received a taxane as their chemotherapy, while roughly 54% of patients received gemcitabine/carboplatin. Twenty-two percent of patients received the same chemotherapy previously in the neoadjuvant/adjuvant setting. Additionally, 29.7% of patients had de novo metastasis, 20.1% had a disease-free interval (DFI) of less than 12 months, and 50% of patients had a DFI of 12 months or longer.

Findings also showed that the 1-year PFS rates were 39.1% and 23.0% with pembrolizumab/chemotherapy and chemotherapy alone, respectively, in patients whose tumors had a PD-L1 CPS of 10 or higher; these rates were 65.0% and 46.9%, respectively, at 6 months. Also, the PFS benefit with patients whose tumors had a PD-L1 CPS of ≥10 was demonstrated across most subgroups, except in those whose DFI was 12 months or longer (HR, 1.00; 95% CI, 0.51-1.95).

"We should take into account that the sample size was very [small], the trial was not designed to look at this subgroup, and we had widely overlapping confidence intervals," Cortes noted with regard to these data.

For patients whose tumors had a PD-L1 CPS of 1 or higher, the 1-year PFS rate with pembrolizumab/chemotherapy was 31.7% versus 19.4% with chemotherapy alone. The 6-month PFS rates in this group was 56.4% and 46.6% for pembrolizumab/chemotherapy and chemotherapy alone, respectively.

In the ITT population, 1-year PFS rates were 29.8% with the addition of pembrolizumab and 20.9% with chemotherapy alone; at 6 months, these rates were 55.4% and 47.8%, respectively. The PFS benefit with pembrolizumab was observed across subgroups in both the ITT population and in those with a PD-L1 CPS of 1 or higher.

Moreover, patients who had a CPS of ≥20, also greatly benefited from pembrolizumab plus chemotherapy, with a median PFS of 9.5 months (HR, 0.61; 95% CI, 0.43-0.87).

Regarding safety, all-grade adverse events (AEs) were similar between arms; grade 3 to 5 AEs were 68.1% and 66.9% in the pembrolizumab and placebo arms, respectively. Additionally, 0.4% (n = 2) of treatment-related AEs (TRAEs) led to death in the pembrolizumab arm versus 0% in the placebo group. Moreover, 18.1% of patients on pembrolizumab/chemotherapy discontinued treatment versus 11.0% of those on chemotherapy alone.

All-grade TRAEs that occurred in at least 20% of patients in either arm included anemia (48.9% with pembrolizumab vs 45.9% with chemotherapy alone), neutropenia (41.1% vs 38.1%, respectively), nausea (39.3% vs 40.9%), alopecia (33.1% vs 33.5%), fatigue (28.5% vs 29.5%), decreased neutrophil count (22.2% vs 26.3%), and increased alanine aminotransferase levels (20.5% vs 16.4%).

Immune-related AEs (irAEs) occurred in 25.6% of patients on the pembrolizumab/chemotherapy arm versus 6.0% of those on the placebo arm; these rates were grade 3 to 5 in 5.2% and 0% of patients, respectively. Additionally, 3.9% of patients on pembrolizumab/chemotherapy discontinued treatment due to irAEs versus 1.1% of those on chemotherapy alone. No irAEs led to death. These all-grade irAEs included hypothyroidism (15.5% with pembrolizumab/chemotherapy vs 3.2% with placebo), hyperthyroidism (4.8% vs 1.1%, respectively), pneumonitis (2.5% vs 0%), colitis (1.8% vs 0.4%), and severe skin reactions (1.8% vs 0.4%).

_References:

_{1. Cortes J, Cescon DW, Rugo HS. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol. 2020;38(suppl 15; abstr 1000). doi:10.1200/JCO.2020.38.15_suppl.1000}

_{2. Merck's Keytruda (pembrolizumab) in combination with chemotherapy met primary endpoint of progression-free survival (PFS) as first-line treatment for metastatic triple-negative breast cancer (mTNBC). News release. Merck. February 12, 2020. Accessed February 12, 2020. bit.ly/2vw4yaH.}

_{3. Nanda R, Chow LQM, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34:2460-2467. doi:10.1200/JCO.2015.64.8931}

_{4. Adams S, Schmid P, Rugo HS, et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann Oncol. 2019;30:397-404. doi:10.1093/annonc/mdy517}

_{5. Adams S, Loi S, Toppmeyer D, et al. Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study. Ann Oncol. 2019;30:405-411. doi:10.1093/annonc/mdy518}

_{6. Cortes J, Lipatov O, Im S, et al. KEYNOTE-119: phase 3 study of pembrolizumab (pembro) versus single-agent chemotherapy (chemo) for metastatic triple-negative breast cancer (mtnbc). Ann Oncol. 2019;30(suppl 5):v851-v934. doi:0.1093/annonc/mdz394}

_{7. Schmid P, Salgado R, Park YH. Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study. Ann Oncol. 2020;31(5):569-581. doi: 10.1016/j.annonc.2020.01.072}

_{8. Schmid P, Park YH, Ferreira M, et al. KEYNOTE-522: phase 3 study of neoadjuvant pembrolizumab + chemotherapy versus placebo + chemotherapy, followed by adjuvant pembrolizumab versus placebo for early triple-negative breast cancer: pathologic complete response in key subgroups and by treatment exposure and residual cancer burden. Presented at: 2019 San Antonia Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX.}