KEYNOTE unlocks immunotherapy OS benefit in metastatic TNBC, effective in early disease

Natalia Reoutova
14 Oct 2021
KEYNOTE unlocks immunotherapy OS benefit in metastatic TNBC, effective in early disease

Triple-negative breast cancer (TNBC) is considered one of the highest-risk subtypes of breast cancer and has a dismal prognosis. Due to the lack of targetable oestrogen, progesterone and HER2 receptors, there is a paucity of effective therapies, with PARP and PI3K inhibitors also failing to significantly improve overall survival (OS) in recent trials. [N Engl J Med 2017;377:523-533; Cancer Lett 2021;497:100-111; Loibl S, et al, ESMO 2021, abstract 119O]

Management mainly involves definitive surgery plus conventional chemotherapy with platinum compounds, taxanes and anthracyclines, or breast-conserving surgery plus local radiotherapy in better-prognosis patients. However, the response achieved is rarely long-lasting with very limited efficacy in metastatic and relapsed disease. [Expert Opin Ther Targets 2016;20:705-720]

Recent advances in tumour microenvironment research indicate higher levels of lymphocyte infiltration and PD-L1 expression in TNBC than in other breast cancer subtypes. [Cancer Res 2021;81:4290-4304; Nat Commun 2020;11:1669; Life Sci 2020;259:118297] Furthermore, TNBC has a high degree of genomic instability, leading to a greater number of somatic mutations, which frequently present as neoantigens. [Breast 2016;29:241-250] Taken together, these findings suggest immunotherapy’s potential in the treatment of this particular population of breast cancer patients.

While TNBC immunotherapy has recently experienced a setback with the withdrawal of atezolizumab following a lack of progression-free survival (PFS) or OS benefit in the IMpassion131 trial, results of the KEYNOTE-522 and KEYNOTE-355 trials re-affirm the transformative role of immunotherapy in this indication. [Ann Oncol 2021;32:994-1004]

KEYNOTE-522: Improved EFS and pCR in early-stage TNBC

The latest interim analysis of the pivotal phase III KEYNOTE-522 trial, presented at the European Society for Medical Oncology (ESMO) Virtual Plenary in July 2021, demonstrated significant improvements in clinical outcomes with pembrolizumab plus chemotherapy vs chemotherapy alone as a neoadjuvant/adjuvant treatment of TNBC. [Schmid P, et al, ESMO Virtual Plenary 2021, abstract VP7-2021] It was the first large, randomized, phase III trial to report a statistically significant and clinically meaningful event-free survival (EFS) benefit in this population.

The trial enrolled 1,174 patients with stage II or III TNBC. More than 80 percent of patients expressed PD-L1 (ie, combined positive score [CPS] ≥10), and about half had lymph node involvement. Patients were randomly assigned 2:1 to receive pembrolizumab plus chemotherapy or placebo plus chemotherapy.

Patients received neoadjuvant pembrolizumab 200 mg or placebo every 3 weeks plus weekly paclitaxel and weekly or 3-weekly carboplatin for four cycles, followed by pembrolizumab 200 mg or placebo every 3 weeks plus cyclophosphamide and either doxorubicin or epirubicin every 3 weeks for four cycles prior to surgery. This regimen was followed by adjuvant treatment with nine cycles of pembrolizumab or placebo every 3 weeks.

After a median follow-up of 39 months, the pembrolizumab arm had a 37 percent reduction in EFS events vs the placebo arm (hazard ratio [HR], 0.63; 95 percent confidence interval [CI], 0.48 to 0.82; p=0.00031). The 3-year EFS rate was 84.5 percent with pembrolizumab plus chemotherapy compared with 76.8 percent with chemotherapy alone. Pembrolizumab also improved pathologic complete response (pCR) rate vs placebo (64.8 percent vs 51.2 percent; p=0.00055).

“KEYNOTE-522 met its dual primary endpoints,” said lead investigator Dr Peter Schmid of the Centre for Experimental Cancer Medicine, Barts Cancer Institute, London, UK. “These results support pembrolizumab plus platinum-containing neoadjuvant chemotherapy, followed by adjuvant pembrolizumab, as a new standard-of-care [SoC] treatment regimen for patients with high-risk, early-stage TNBC.”

In prespecified exploratory subgroup analyses, the 3-year EFS benefit seen with pembrolizumab was independent of PD-L1 expression or achievement of pCR. Following a pCR, the EFS rate was 94.4 percent with pembrolizumab plus chemotherapy vs 92.5 percent with placebo plus chemotherapy. In patients without a pCR, these rates were 67.4 percent vs 56.8 percent. “Patients with residual disease have a substantially higher EFS rate if treated with pembrolizumab,” commented Schmid.

While the OS data were immature at the latest analysis, the researchers observed a trend for improved OS in the pembrolizumab vs placebo arm (3-year OS rates, 89.7 percent vs 86.9 percent).

Asian subanalysis

Among breast cancer patients, prognosis and response to systemic chemotherapy have been reported to differ by ethnicity. Potentially, response to immunotherapy may differ between Asian and non-Asian TNBC patients, both in terms of efficacy and tolerability. [Int J Cancer 2021;doi:10.1002/ijc.33463]

A subgroup analysis of KEYNOTE-522, presented at the ESMO Asia Virtual Congress 2020, showed that the combination of pembrolizumab and chemotherapy significantly increased pCR in Asian patients with TNBC. [Annals of Oncology 2020;31(suppl_6):S1241-S1254] At a median follow-up of 13.0 months, the pCR rate among the first 125 Asian patients was 59 percent in those receiving pembrolizumab vs 40 percent in those receiving placebo.

Improvements in pCR were seen irrespective of PD-L1 CPS score. However, they were most notable in those patients with node-positive disease at study entry (>30 percent increase in pCR).


The safety profile of pembrolizumab plus chemotherapy observed in KEYNOTE-522 was consistent with known profiles of each regimen, with no new safety concerns identified. Grade 3 or 4 treatment-related adverse events (TRAEs) were observed in 77.1 percent of patients in the pembrolizumab plus chemotherapy arm and in 73.3 percent of patients receiving chemotherapy alone. Treatment-related toxicity led to death in four patients who received pembrolizumab and in one patient in the chemotherapy alone arm.

Among Asian patients, the incidence of grade ≥3 TRAEs was 75 percent with pembrolizumab and 76 percent with placebo. No deaths occurred with either treatment.

KEYNOTE-355: OS benefit in metastatic TNBC

The phase III KEYNOTE-355 trial examined pembrolizumab in combination with investigator's choice of either nab-paclitaxel, paclitaxel or gemcitabine plus carboplatin vs placebo plus chemotherapy in patients with previously untreated, locally recurrent, inoperable or metastatic TNBC.

A total of 847 patients were randomized 2:1 to receive placebo (n=281) or pembrolizumab (n=566) (200 mg on day 1 of each 21-day treatment cycle), in combination with either nab-paclitaxel (100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle), paclitaxel (90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle) or  gemcitabine (1,000 mg/m2) and carboplatin (area under the curve [AUC] 2) on days 1 and 8 of each 21-day cycle. [Ann Oncol 2021;32(suppl_5):S1283-S1346]

The coprimary endpoints of the trial were PFS and OS in patients with PD-L1–positive tumours (CPS ≥10) and in the intent-to-treat (ITT) population. Key secondary endpoints included objective response rate (ORR), duration of response (DoR), disease control rate (DCR), and safety.

At a median follow-up of 44.1 months, pembrolizumab plus chemotherapy significantly improved OS vs chemotherapy alone in patients with CPS ≥10 tumours by nearly 7 months (median, 23.0 months vs 16.1 months), and reduced the risk of death by 27 percent (HR, 0.73; 95 percent CI, 0.55 to 0.95; p=0.0093). Notably, there was no added benefit with pembrolizumab when applying a cutoff of CPS ≥1.

“These results support pembrolizumab plus chemotherapy as a new SoC treatment regimen for patients with locally recurrent, unresectable or metastatic TNBC whose tumors express PD-L1 with CPS ≥10,” said presenter Dr Hope Rugo of the University of California Helen Diller Family Comprehensive Cancer Center in San Francisco, US.

Updated PFS results were consistent with those previously reported. In the CPS ≥10 group, median PFS was 9.7 months in the pembrolizumab arm vs 5.6 months in the placebo arm (HR, 0.66; 95 percent CI, 0.50 to 0.88).

“These findings are really significant in a disease where OS has remained poor and unchanged for years,” commented Dr Maria of the University of Padua, Italy. “Due to immunotherapy’s mode of action, the OS gain can often outperform the PFS gain, and this is what we saw in KEYNOTE-355 – with advantages for pembrolizumab over chemotherapy of 4 months and 7 months for PFS and OS, respectively.”

The secondary endpoints of ORR and DCR were higher with pembrolizumab plus chemotherapy vs placebo plus chemotherapy, with the greatest treatment effect seen in CPS ≥10 patients (ORR, 52.7 percent vs 40.8 percent; DCR, 65.0 percent vs 54.4 percent). DoR was also longer in the pembrolizumab plus chemotherapy group, with the longest DoR observed in the CPS ≥10 group (12.8 months vs 7.3 months).


Almost all patients (96.3 percent in the pembrolizumab group and 95.0 percent in the placebo group) had ≥1 TRAE of any grade, while 68.1 percent and 66.9 percent of patients in the two arms, respectively, had ≥1 grade 3–5 TRAE. The most common TRAEs were anaemia, neutropenia, and nausea.

There were two TRAEs that led to death in the pembrolizumab arm, while 18.3 percent of patients in the pembrolizumab arm and 11.0 percent in the placebo arm discontinued treatment due to toxicity. Immune-mediated AEs occurred in 26.5 percent of pembrolizumab-treated patients and in 6.4 percent of patients in the placebo group, the most common of which were hypothyroidism and hyperthyroidism.

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